CN101977595A

CN101977595A - Compositions for the treatment and prevention of eyelid swelling

Info

Publication number: CN101977595A
Application number: CN2008801191850A
Authority: CN
Inventors: M·J·查平; M·B·艾贝尔森; K·J·莱恩; G·明诺
Original assignee: ACIEX Inc
Current assignee: ACIEX Inc
Priority date: 2007-11-08
Filing date: 2008-11-06
Publication date: 2011-02-16
Also published as: WO2009061431A2; JP2011503061A; BRPI0819105A2; CA2705050A1; AU2008325214A1; EP2219630A2; WO2009061431A3; MX2010005012A

Abstract

The invention features topical formulations comprising an osmotically active agent and/or a vasoconstrictor and/or an astringent agent for the treatment and prevention of eyelid swelling, and methods of use thereof.

Description

The compositions that is used for the treatment of and prevents eyelid swelled

Related application

The application requires to enjoy the priority that the applying date is the U.S. Provisional Application No.61/007511 on November 8th, 2007, and the full content in the above-mentioned document all is introduced into as a reference in the present invention.

Invention field

The present invention relates to new ophthalmic composition and be used for method that eyelid swelled is effectively prevented and treated.Concrete, the present invention relates to a kind of ophthalmic composition, described compositions comprises a kind of infiltrative active agent, a kind of astringent, a kind of vasoconstrictor, or the combination of mentioned reagent, wherein said compositions can effectively be used for the prevention and the treatment of eyelid swelled.In addition the present invention also relates to the host that these needs are arranged and uses such method for compositions.

Background technology

The inflammation of eyelid swelled and eyelid is in the meaning that all has secular meaning and short-term aspect quality of life of histology influence, patient and the general patient's comfortableness.Described human eyelid is to be formed by the layer the most clear and legible in skin layer the thinnest in the described body, described tissue and the muscle and the collagen fibers of described most fragile.Because these accurate skin layers, described eyelid is very easy to be subjected to the influence of swelling, acute inflammation and contingent long-term damage.

Eyelid has several important roles, thereby allows eyes to bring into play the function that it should have.They are protected eyes and protect by reflexive closed pair cornea.This just mechanism often stops granule or foreign body to enter within the eyes and stops issuable damage.Described eyelid is controlled the amount that enters the described light in the eyes equally, just as the working method of the shutter in the photographing unit.They can increase the component (via the informer) in the described tear film equally and keep the distribution of described lubricating fluid around the described eyes, and this to keep effect be to be used for carrying out by their disseminating in the nictation process.Eyelid not only keep eye health aspect played very enormous function, and also playing very enormous function aspect the allomeric function of described visual system.When this vital protection mechanism has produced inflammation, the described vision health of described individuality just has been subjected to threat.

Repeatability that eyelid carried out is stretched and damage can cause the temporary formation of sagging, sagging skin layer, wherein said repeatability stretches and damage causes by having various etiologic etiological swelling, and described skin layer is positioned at the top and the below of eyes.The swelling of this eyelid can provide a kind of and not make us very much the outward appearance of expecting and even can produce restriction to the visual field.Although these signs mostly just are temporary, because the accumulation that it is carried out when recurring each time makes the described actual damage that occurs on described physiology's level and the anatomy level finally can cause nonvolatil change.

When vision health was estimated, the symptom of this eyelid swelled was not considered to the matter of utmost importance that should be concerned about usually, although it is a main problem for many patients, doctor and researcher.The eyelid swelled in early morning is very general, and it has obtained social concerns widely equally except being subjected to relating to the concern of patient health.2002, in the U.S., eyelid surgical operation (229092) and Botulinum toxin injection (1658667) is two the most common operations that plastic surgeon is finished, this The fact has been fully proved show the patient for expansible, sagging that eyelid produced was worried and can not put up with degree completely.Although have significant expectation for the appearance that reduces blepharoedema, for described symptom, all lack attention all the time.Described symptom is divided among other the sign and symptom usually, but in clinical research seldom with it as a primary variable, because it is difficult to accurately measure from historical facts.Various optic hyperesthesia disease drug, olopatadine (olopatadine) 0.1% (Pa Tanluo Patanol) for example, begun to alleviate the eyelid swelled relevant with anaphylaxis conjunctivitis, can be directly and effectively be used for resisting the medicine of this symptom specially but do not have.Because the necessary being of multiple situation like this is arranged socially, and a kind of Therapeutic Method that can directly exert an influence to described eyelid swelled disease is necessary.

Summary of the invention

The invention provides the new compositions and the method that are used for the treatment of and prevent eyelid swelled, wherein said eyelid swelled is the nonallergic eyelid swelled particularly.In some embodiments, the ophthalmic preparation that provides new part to use, described ophthalmic preparation comprises a kind of infiltrative active agent and/or a kind of vasoconstrictor and/or a kind of astringent.Especially, the invention provides the ophthalmic preparation that use acceptable part, described ophthalmic preparation comprises the combination of a kind of infiltrative active agent and/or a kind of vasoconstrictor and/or a kind of astringent, their synergitic playing a role are in order to treat eyelid swelled and to prevent.Except other aspect, the described special effect that these preparations had is owing to the synergy that combination produced that is present in the described component among them.Synergitic the playing a role of combination of described infiltrative active agent and/or vasoconstrictor and/or astringent, treat in order to sign and symptom eyelid swelled, this synergitic effect had before never been anticipated to realize in a kind of product that wherein said a kind of product contains each in these independent components.

In one embodiment, the present invention provides a kind of scope of target capacity infiltration molar concentration and/or the scope of weight infiltration molar concentration for described a kind of effective ophthalmic composition preparation, wherein said preparation have a kind of acceptability (promptly, tolerability) comfort curve, in order to eyelid swelled is treated and prevents.In order to possess infiltrative activity, described capacity infiltration molar concentration that a kind of solution had and/or weight infiltration molar concentration must be higher than described capacity infiltration molar concentration and/or the weight infiltration molar concentration that its surrounding has.Capacity infiltration molar concentration refers to the measured value of the infiltration mole of the described solute that exists in every liter of solution, and described weight infiltration molar concentration refers to the measured value of the infiltration mole of the described solute that exists in every kilogram of solvent.Molar concentration and capacity infiltration molar concentration are not what be commonly used in the osmolarity measuring method, because they depend on temperature; That is, the change on the volume can take place along with variation of temperature in water.Those skilled in the art should be easy to recognize, if described concentration very low (example is the concentration of compositions as described in the present invention), so described term capacity infiltration molar concentration and weight infiltration molar concentration be considered to equivalence and when they being applied in the compositions of the present invention, both can be used alternatingly in the present invention.

In common human eye, weight that described human tear film is had infiltration molar concentration is present within the scope that about 250-350 permeates molar concentration/kilogram (mOsm/Kg) in the least, permeate the meansigma methods of molar concentration/kilogram and in the individuality of suffering from the vision disease, can have up to about 450 millis, wherein said vision disease is including, but not limited to, dry eye disorders (its maximum surpasses 700 millis and permeates molar concentration/kilogram).Therefore, in order to bring into play therapeutic efficiency and to alleviate edema, bottom line must constrain in weight that a kind of ophthalmic solution had infiltration molar concentration on the weight infiltration molar concentration level that described people's ocular environment had (that is, about 250 to 450 millis permeate molar concentration/kilogram).Yet, be accompanied by the increase of weight infiltration molar concentration, when instiling, can produce the uncomfortable property of increase.High-caliber ion can activate teleneuron, and teleneuron can cause the vision twinge.Pass through comfort test, the present invention finds that ophthalmic solution should have the weight infiltration molar concentration within the scope of permeating molar concentration/kilogram less than 2000 millis, and be more preferably less than 1050 millis and permeate molar concentration/kilogram, thereby have acceptable, i.e. the comfort curve of tolerability.Therefore, for a kind of for for the drop of preparing in order to the treatment of carrying out eyelid swelled, the scope of described target weight infiltration molar concentration is preferably permeated within molar concentration/kilogram at 200 to 2000 millis, being preferably 250 millis permeates molar concentration/kilogram and permeates in the least molar concentration/kilogram to 1500, be more preferably 260 millis and permeate molar concentration/kilogram to 1250 millis and permeate molar concentration/kilogram, be more preferably 265 millis and permeate molar concentration/kilogram to 1200 millis and permeate molar concentration/kilogram and be more preferably 400 and permeate in the least molar concentration/kilogram and permeate molar concentration/kilogram in the least and be more preferably 500 to 1150 and permeate molar concentration/kilogram in the least and permeate in the least molar concentration/kilogram to 1100.

In some embodiments, compositions of the present invention comprises a kind of infiltrative active agent, and wherein said infiltrative active agent is including, but not limited to a kind of colloid osmotic agent and a kind of crystal osmotic agent.Be suitable for crystal osmotic agent among the compositions of the present invention including, but not limited to sodium chloride (NaCl), glucose, sucrose, glycerol, mannitol, sorbitol, state-promulgated pharmacopoeia level (NF) Polyethylene Glycol 3350, magnesium citrate and lactulose.In some embodiments, the effective dose of described crystal osmotic agent is selected from the group of being made up of following dosage: about 1% sodium chloride to about 10% weight/volume, about 1% glucose to about 10% weight/volume, about 1% glycerol to about 20% weight/volume, about 1% mannitol to about 20% weight/volume, about 1% sucrose, and about 1% sorbitol to about 95% weight/volume to about 95% weight/volume.Preferably, described crystal osmotic agent is a sodium chloride, and described effective dose is about 1% to about 10% weight/volume, is more preferably about 2% to about 5% weight/volume.

Be suitable for colloid osmotic agent among the compositions of the present invention including, but not limited to hetastarch (hetastarch), pentastarch (pentastarch), with the crosslinked gel polypeptide of carbamide, macrodex, Gentran 40, albumin, icodextrin, USP level (American Pharmacopeia rank) bentonite, NF level (state-promulgated pharmacopoeia level) aluminium magensium silicate 2A type (MgAl silicate NF type 2A), NF level (state-promulgated pharmacopoeia level) alginic acid/sodium alginate, microcrystalline Cellulose and NF level (state-promulgated pharmacopoeia level) sodium carboxymethyl cellulose, carbomer and gellan gum.

In some embodiments, the effective dose of described colloid osmotic agent is selected from the group of being made up of following dosage: about 1% hetastarch to about 10% weight/volume (hetastarch), about 1% pentastarch (pentastarch) to about 20% weight/volume, about 1% macrodex to about 10% weight/volume, about 1% Gentran 40 to about 10% weight, about 1% albumin, and about 1% microcrystalline Cellulose to about 50% weight/volume to about 50% weight/volume.

Be suitable for other osmotic agent among the method for the present invention including, but not limited to magnesium sulfate, magnesium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, acid phosphatase potassium, calcium lactate, Magnesium succinate, the carbohydrate of tartaric acid and solubility is melitriose for example, glucose, caffeine, carbomer 934 P, tannic acid, ascorbic acid, glucosan-40000, inulin, menthol, polysorbate80, and the mixture of mentioned reagent.In some embodiments, the effective dose of described osmotic agent is about 0.001% caffeine to about 10% weight/volume, about 0.001% carbomer 934 P to about 10% weight/volume, about 0.001% tannic acid to about 10% weight/volume, about 0.001% ascorbic acid to about 10% weight/volume, about 0.001% glucosan-40000 to about 10% weight/volume, about 0.001% inulin to about 10% weight/volume, about 0.001% menthol to about 10% weight/volume, about 0.001% Polyoxyethylene Sorbitan Monooleate, or the mixture of mentioned reagent to about 10% weight/volume.

In some embodiments, comprise a kind of vasoconstrictor in the compositions of the present invention.Be suitable for described vasoconstrictor among the compositions of the present invention including, but not limited to naphazoline, oxymetazoline, phenylephrine, tetrahydrozoline, and have vasoactive can be as other reagent of α receptor stimulating agent.A kind of preferred embodiment in, described vasoconstrictor is naphazoline and described effective dose about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, be more preferably for about 0.01% to about 0.5% weight/volume, even be more preferably for about 0.01% to about 0.2% weight/volume, even be more preferably for about 0.09% to about 0.1% weight/volume.Another preferred embodiment in, the described vasoconstrictor that is suitable among the compositions of the present invention is an oxymetazoline, and described effective dose about 0.01% to the scope of about 0.2% weight/volume, what be more preferably is 0.01% to about 0.1% weight/volume, in addition be more preferably for about 0.03% to about 0.05% weight/volume.Another preferred embodiment in, be suitable for described vasoconstrictor among the compositions of the present invention and be phenylephrine and described effective dose about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, be more preferably for about 0.01% to about 0.5% weight/volume, even be more preferably for about 0.05% to about 0.2% weight/volume.

In other embodiment, comprise a kind of convergence reagent in the compositions of the present invention.Be suitable for convergence reagent among the compositions of the present invention including, but not limited to Radix Hamamelidis Mollis, zinc sulfate, silver sulfate, vegetable tannins acid, oak bark extract, five galloyl glucoses, Alumen, burow's solution (burow ' s solution), black brambles extract, european bird cherry extract and natural flavonoid.Preferably, described convergence reagent is Radix Hamamelidis Mollis and/or zinc sulfate and described effective dose about 0.001% to the scope of about 10% weight/volume, preferably about 0.01% to about 5% weight/volume, be more preferably for about 0.1% to about 1% weight/volume, even be more preferably for about 0.2% to about 0.75% weight/volume.

In a certain embodiment, comprise the combination of a kind of infiltrative active agent and a kind of vasoconstrictor in the compositions of the present invention.In one embodiment, described infiltrative active agent is that sodium chloride or glycerol and described vasoconstrictor are naphazoline or oxymetazoline.Preferably, described sodium chloride is to exist with about 1% scope to about 10% weight/volume, be more preferably for about 2% to about 5% weight/volume; Described glycerol is to exist with about 1% scope to about 30% weight/volume, preferably 1% to about 20% weight/volume, be more preferably for about 1% to about 10% weight/volume, even be more preferably for about 5% to about 8% weight/volume; Described naphazoline is to exist with about 0.01% scope to about 0.5% weight/volume, be more preferably for about 0.01% to about 0.2% weight/volume; And described oxymetazoline is to exist with about 0.01% scope to about 0.2% weight/volume, be more preferably for about 0.01% to about 0.1% weight/volume, even be more preferably for about 0.03% to about 0.05% weight/volume.

For example, the sodium chloride that described infiltrative active agent is 3% weight/volume or the glycerol of 7.5% weight/volume, and vasoconstrictor is the naphazoline of 0.09% weight/volume or the oxymetazoline of 0.05% weight/volume.In one embodiment, described osmotic agent is that the glycerol and the described vasoconstrictor of 7.5% weight/volume are the naphazolines of 0.09% weight/volume.In another embodiment, described osmotic agent is that the glycerol and the described vasoconstrictor of 7.5% weight/volume is the oxymetazoline of 0.05% weight/volume.In another embodiment, described osmotic agent is that the sodium chloride and the described vasoconstrictor of 3% weight/volume is the naphazoline of 0.09% weight/volume.In another embodiment, described osmotic agent is that the sodium chloride and the described vasoconstrictor of 3% weight/volume is the oxymetazoline of 0.05% weight/volume.

In a kind of specific embodiment, comprise a kind of carrier of medicine acceptability and the naphcon of 0.9 mg/ml in the compositions of the present invention, the sodium chloride of 30 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions is 6.0.

In another specific embodiment, comprise a kind of carrier of medicine acceptability and the naphcon of 0.9 mg/ml in the compositions of the present invention, the glycerol of 75 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions is 6.0.

In another specific embodiment, comprise a kind of carrier of medicine acceptability and the oxymetazoline hydrochloride of 0.5 mg/ml in the compositions of the present invention, the sodium chloride of 30 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions is 6.0.

In another specific embodiment, comprise a kind of carrier of medicine acceptability and the oxymetazoline hydrochloride of 0.5 mg/ml in the compositions of the present invention, the glycerol of 75 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions is 6.0.

In some embodiments, comprise the combination of a kind of infiltrative active agent and a kind of vasoconstrictor in the compositions of the present invention, wherein said infiltrative active agent is selected from the group of being made up of following reagent place: caffeine, carbomer 934 P, tannic acid, ascorbic acid, Gentran 40 000, inulin, mannitol, menthol, and polysorbate80, and wherein said vasoconstrictor is selected from the group of being made up of following reagent place: naphazoline, oxymetazoline, phenylephrine, and tetrahydrozoline.

Choose wantonly, described infiltrative active agent, and/or vasoconstrictor, and/or convergence reagent can make up with various other reagent, in order to eyelid swelled is treated and prevent, wherein said various other reagent are including, but not limited to other vasoconstrictor, tear substitute, antiallergic reagent, hydryllin, mast cell stabilizers, on-steroidal AID (NSAID), steroid, anti-inflammatory agent, antioxidation reagent, infection reagent, cholinomimetic energy reagent, and the combination of mentioned reagent.

The preparation of compositions described in the present invention can be become the following form that is used to carry out local application: solution, suspension, oil, gel viscosity or quasi-viscous, emulsion, liposome, washing liquid, ointment, cream, gel, ointment, powder, continue to discharge or slow preparation or the implant that discharges, the eyelid washing liquid, the perhaps solid composite of other types or semi-solid combination, and the form of sprayable form or propellant.Compositions of the present invention can be formulated into to carrying out the form of acute administration or chronic administration, is used among the treating and/or preventing of eyelid swelled.

Feature of the present invention is the new method of using such preparation eyelid swelled to be treated and prevent equally.In some embodiments, the described method of in host eyelid swelled being treated and preventing comprises local application from compositions of the present invention to host's ocular surface that carry out, in order to treatment and prevention eyelid swelled.In other embodiment, comprise in the method for the present invention to host's palpebra interna and/or outside eyelid carry out the local application of compositions of the present invention, in order to treatment and prevention eyelid swelled.

In some embodiments, the described method of in host eyelid swelled being treated and preventing comprises: at least a active agent that is selected from the group of being made up of following reagent place of using effective dose on described host's inner eye corner or the tail of the eye/eyelid surface: a kind of infiltrative active agent, a kind of vasoconstrictor, and a kind of convergence reagent.

In another embodiment, the described method of in host eyelid swelled being treated and preventing comprises: use effective dose on described host's inner eye corner or the tail of the eye/eyelid surface at least two kinds are selected from a kind of infiltrative active agent, a kind of vasoconstrictor and a kind of combination of agents that restrains in the reagent.In a kind of specific embodiment, with the combined administration of a kind of infiltrative active agent of effective dose and a kind of vasoconstrictor to described host's inner eye corner or the tail of the eye/eyelid surface.For example, described infiltrative active agent is that sodium chloride or glycerol and described vasoconstrictor are naphazoline or oxymetazoline.

In one embodiment, the compositions that comprises the naphazoline of the glycerol of using 7.5% weight/volume on described host's inner eye corner or the tail of the eye/eyelid surface and 0.09% weight/volume in the method for the present invention is in order to treat eyelid swelled and to prevent.In another embodiment, the compositions that comprises the oxymetazoline of the glycerol of using 7.5% weight/volume on described host's inner eye corner or the tail of the eye/eyelid surface and 0.05% weight/volume in the method for the present invention is in order to treat eyelid swelled and to prevent.In another embodiment, the compositions that comprises the naphazoline of the sodium chloride of using 3% weight/volume on described host's inner eye corner or the tail of the eye/eyelid surface and 0.09% weight/volume in the method for the present invention is in order to treat eyelid swelled and to prevent.In another embodiment, the compositions that comprises the oxymetazoline of the sodium chloride of using 3% weight/volume on described host's inner eye corner or the tail of the eye/eyelid surface and 0.05% weight/volume in the method for the present invention is in order to treat eyelid swelled and to prevent.

In a kind of specific embodiment, comprise in the method for the present invention on described host's inner eye corner or the tail of the eye/eyelid surface and use a kind of like this compositions, in order to eyelid swelled is treated and prevents: the naphcon of 0.9 mg/ml, the sodium chloride of 30 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, and a kind of carrier of medicine acceptability, the pH of wherein said compositions is 6.0.

In another specific embodiment, comprise in the method for the present invention on described host's inner eye corner or the tail of the eye/eyelid surface and use a kind of like this compositions, in order to eyelid swelled is treated and prevents: the naphcon of 0.9 mg/ml, the glycerol of 75 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, and a kind of carrier of medicine acceptability, (whole pH is 6.0).

In another specific embodiment, comprise in the method for the present invention on described host's inner eye corner or the tail of the eye/eyelid surface and use a kind of like this compositions, in order to eyelid swelled is treated and prevents: the oxymetazoline hydrochloride of 0.5 mg/ml, the sodium chloride of 30 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, and a kind of carrier of medicine acceptability, (whole pH is 6.0).

In another specific embodiment, comprise in the method for the present invention on described host's inner eye corner or the tail of the eye/eyelid surface and use a kind of like this compositions, in order to eyelid swelled is treated and prevents: the oxymetazoline hydrochloride of 0.5 mg/ml, the glycerol of 75 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, and a kind of carrier of medicine acceptability, (whole pH is 6.0).

In some embodiments, comprise in the method for the present invention on described host's inner eye corner or the tail of the eye/eyelid surface and use a kind of compositions, in order to eyelid swelled is treated and prevents, wherein said compositions is combined by a kind of infiltrative active agent and a kind of vasoconstrictor, wherein said infiltrative active agent is selected from the group of being made up of following reagent place: caffeine, carbomer 934 P, tannic acid, ascorbic acid, Gentran 40 000, inulin, mannitol, menthol, and polysorbate80, and wherein said vasoconstrictor is selected from the group of being made up of following reagent place: naphazoline, oxymetazoline, phenylephrine, and tetrahydrozoline.

Can use such preparation with a kind of suitable dosage, in order to eyelid swelled is treated and prevents, wherein said dosage depends on absorption rate, deactivation speed and the discharge rate of described medicine, and by day, night, be about to go to bed before and/or be about to wake up before the delivery rate of described chemical compound.Can carry out using of acute purposes or chronic purposes to such reagent equally, in order to eyelid swelled is treated and prevent.

Further, the invention is characterized in the method for the variation of using a kind of controlled object lens commercial measurement eyelid swelled, utilized scanning imaging technology (for example, 3D scanning technique) in the wherein said object lens technology.Such method can be carried out a kind of objective and accurate quantification to fluctuation every day of eyelid swelled.

Further, the invention is characterized in a kind of test kit, described test kit is used for described preparation is transported, stores or uses, and described method is implemented.Other features that the present invention had and advantage will become apparent by following detailed and claim.

Description of drawings

The a part of form that contains the medical conditions that can show eyelid swelling in the accompanying drawing 1, wherein the details for this performance of each disease is illustrated, and is illustrated for other symptoms of this disease.

Accompanying drawing 2 is described is a kind of osmotic agent to effect that eyelid swelled played.

Accompanying drawing 3A-3L is one group of linear schedule, description be a result who uses 0.1% naphazoline that the institute that early morning of 11 hosts, eyelid swelled was treated is obtained.In each width of cloth in accompanying drawing 3A-3L, represent that time point is represented is to have carried out institute's elapsed time after the instillation of described research medicine by the baseline logarithm value.For each host, use naphcon (0.1%) that its right eye has been carried out treating (circle also is represented as " OD "), and its left eye (square also is represented as " OS ") is not received treatment.

Accompanying drawing 4A-4G is one group of linear schedule, being and estimating the result that 5% sodium chloride ophthalmic solution obtains the institute that early morning of 6 hosts, eyelid swelled was treated of description.In each width of cloth in accompanying drawing 4A-4G, represent by the baseline logarithm value, error bars representative be a kind of standard error, and time point represents is to have carried out institute's elapsed time after the instillation of described research medicine.For each host, any eyes are not treated at the baseline place, the sodium chloride ophthalmic solution of use 5% has carried out treating (circle also is represented as " OD ") to its right eye, and its left eye (square also is represented as " OS ") is not received treatment.

Accompanying drawing 5 is linear schedules, that describe is a result that the institute that the eyelid swelled in early morning is treated is obtained, wherein in described research, the effect (and the matched group for the treatment of) that the sodium chloride of the effect that compositions had of naphazoline with a kind of 0.1% and 5% sodium chloride solution and 0.1% naphazoline and 5% is had respectively compares.

Accompanying drawing 6 is bar charts, description be in the research shown in the accompanying drawing 5, the result that combination produced of described 0.1% naphazoline and 5% sodium chloride.

Accompanying drawing 7A is a form, combination preparation and each independent comparison of carrying out of component separately (the 1st hurdle) of having summarized the naphazoline of 5% sodium chloride and 0.1%, test for the effect that alleviates the eyelid swelled in early morning, the weight infiltration molar concentration (the 2nd hurdle) of described each test object, corresponding test object gives that the eyelid swelled in early morning brings alleviates degree (the 3rd hurdle), the contrast eyes early morning eyelid swelled the degree that alleviates (do not have test object, the 4th hurdle), the normalize that alleviates degree (normalized) percent (the 5th hurdle) that brings to eyelid swelled, and the standard error that departs from (the 6th hurdle); Accompanying drawing 7B is a bar chart, description to be each test object alleviate degree to what eyelid swelled was brought.

Accompanying drawing 8 is bar charts, that describe is a result that institute is obtained, wherein in described research, the effect that the compositions that is dissolved in the naphcon (0.05%) in 5% the sodium chloride ophthalmology ointment was had in the eyelid swelled in 4 hosts' of treatment early morning is estimated.

Accompanying drawing 9 is bar charts, that describe is a result that institute is obtained, wherein in described research, the effect that the compositions that is dissolved in the naphcon (0.1%) in 2.5% the sodium chloride ophthalmic solution was had in the eyelid swelled in 6 hosts' of treatment early morning is estimated.Error bars has been represented a kind of standard error.

Accompanying drawing 10 is bar charts, that describe is a result that institute is obtained, wherein in described research, the effect that the compositions that is dissolved in the naphcon (0.1%) in 50% the sucrose solution was had in the eyelid swelled in 6 hosts' of treatment early morning is estimated.Error bars has been represented a kind of standard error.

Accompanying drawing 11A is a form, combination preparation and each independent comparison of carrying out of component separately (the 1st hurdle) of having summarized the naphazoline of 50% sucrose and 0.1%, test for the effect that alleviates the eyelid swelled in early morning, the weight infiltration molar concentration (the 2nd hurdle) of described each test object, corresponding test object gives that the eyelid swelled in early morning brings alleviates degree (the 3rd hurdle), the contrast eyes early morning eyelid swelled the degree that alleviates (do not have test object, the 4th hurdle), the normalize that alleviates degree (normalized) percent (the 5th hurdle) that brings to eyelid swelled, and the standard error that departs from (the 6th hurdle); Accompanying drawing 11B is a bar chart, description to be each test object alleviate degree to what eyelid swelled was brought.

Accompanying drawing 12 is linear schedules, description be the making progress naturally of eyelid swelled in early morning in research participant's right eye (OD), left eye (OS) and eyes (OU).In this test, do not treat.

Accompanying drawing 13 is bar charts, description be a result that institute is obtained, wherein in described research, the effect that 0.1% the phenylephrine ointment that the part is used was had in the eyelid swelled in 6 hosts' of treatment early morning is estimated.Error bars has been represented a kind of standard error.

Accompanying drawing 14A is a bar chart, that describe is a result that institute is obtained, wherein in described research, the effect that the compositions of the naphcon (0.1%) in the mannitol ophthalmic solution that is dissolved in 5% sodium chloride and 12.5% was had in the eyelid swelled in 6 hosts' of treatment early morning is estimated.Error bars has been represented a kind of standard error; Accompanying drawing 14B is a form, combination preparation and each independent comparison of carrying out of component separately (the 1st hurdle) of having summarized the naphcon (0.1%) in the mannitol ophthalmic solution that is dissolved in 5% sodium chloride and 12.5%, the weight infiltration molar concentration (the 2nd hurdle) of described each test object, corresponding test object gives that the eyelid swelled in early morning brings alleviates degree (the 3rd hurdle), the contrast eyes early morning eyelid swelled the degree that alleviates (do not have test object, the 4th hurdle), the normalize that alleviates degree (normalized) percent (the 5th hurdle) that brings to eyelid swelled, and the standard error that departs from (the 6th hurdle); Accompanying drawing 14C is a bar chart, description to be each test object alleviate degree to what eyelid swelled was brought.

Accompanying drawing 15 is linear schedules, description be a result that institute is obtained, wherein in described research, the effect that the mannitol ophthalmic solution to 12.5% was had in the eyelid swelled in 6 hosts' of treatment early morning is estimated.Error bars has been represented a kind of standard error.

Accompanying drawing 16A is a form, following combination preparation and each independent comparison of carrying out of component separately (the 1st hurdle) have been summarized: the combination preparation of 5% sodium chloride and 0.1% naphazoline, the combination preparation of 50% sucrose and 0.1% naphazoline, and 5% sodium chloride, the combination preparation of 12.5% mannitol and 0.1% naphazoline, test for the effect that alleviates the eyelid swelled in early morning, the weight infiltration molar concentration (the 2nd hurdle) of described each test object, corresponding test object gives that the eyelid swelled in early morning brings alleviates degree (the 3rd hurdle), the contrast eyes early morning eyelid swelled the degree that alleviates (do not have test object, the 4th hurdle), the normalize that alleviates degree (normalized) percent (the 5th hurdle) that brings to eyelid swelled, and the standard error that departs from (the 6th hurdle); Accompanying drawing 16B is a bar chart, description to be each test object alleviate degree to what eyelid swelled was brought.

Accompanying drawing 17 is bar charts, description be a result that institute is obtained, wherein in described research, the effect that the sucrose ophthalmic solution to 50% was had in the eyelid swelled in six hosts' of treatment early morning is estimated.Error bars has been represented a kind of standard error.

Accompanying drawing 18A is a form, expression be weight infiltration molar concentration and the average comfort level level that various ophthalmic solution has.Accompanying drawing 18B is a linear schedule, what describe is that (with 0-10 is numerical range for the six kinds of different weight that ophthalmic preparation had infiltration molar concentrations and the dependency between the comfort level, (0 expression is the most comfortable, 10 expressions are the most uncomfortable)), wherein said six kinds of different ophthalmic preparations have and are present in about 800 millis and permeate molar concentration/kilogram to the weight that 2400 millis permeate within the scope of molar concentration/kilogram and permeate molar concentration.

Accompanying drawing 19 is bar charts, expression be various ophthalmic preparation (" Oxy " representative be oxymetazoline; " Naph " representative be naphazoline) the average comfort level level that had.

Accompanying drawing 20 is linear schedules, description be 20 hosts' average baselining eyelid swelled score, described score be based on individual regional eyelid swelled and the ratio of globality eyelid swelled produce.At night and second morning after waking up described eyelid swelled is estimated (baseline), be the evaluation that interval carried out a hour altogether after this with ten minutes.

Accompanying drawing 21 is linear schedules, description be 19 hosts in 6 days time night eyelid swelled and early morning eyelid swelled average globality score.In the numerical range of 0-3 (0=does not exist, the complete swelling of 3=) eyelid swelled of globality is carried out the evaluation of subjectivity.

Accompanying drawing 22 is linear schedules, what describe is the average eyelid swelled that takes place in the zone 1 of described human eyelid, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: carry out the instillation of one 0.09% naphazoline/3% sodium chloride in eyes, and carry out the instillation (N=12) of placebo in other eyes.Within 60 minutes time, described eyelid swelled is estimated.

Accompanying drawing 23 is linear schedules, what describe is the average eyelid swelled that takes place in the zone 2 of described human eyelid, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: carry out the instillation of one 0.09% naphazoline/3% sodium chloride in eyes, and carry out the instillation (N=10) of placebo in other eyes.Within 60 minutes time, described eyelid swelled is estimated.

Accompanying drawing 24 is linear schedules, what describe is the average eyelid swelled that takes place in the zone 3 of described human eyelid, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: carry out the instillation of one 0.09% naphazoline/3% sodium chloride in eyes, and carry out the instillation (N=15) of placebo in other eyes.Within 60 minutes time, described eyelid swelled is estimated.

Accompanying drawing 25 is linear schedules, what describe is the average eyelid swelled that takes place in the zone 4 of described human eyelid, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: carry out the instillation of one 0.09% naphazoline/3% sodium chloride in eyes, and carry out the instillation (N=16) of placebo in other eyes.Within 60 minutes time, described eyelid swelled is estimated.

Accompanying drawing 26 is linear schedules, what describe is average globality eyelid swelled, before wherein said eyelid swelled occurs in and instils (baseline) and instil after, wherein said instillation is: carry out the instillation of one 0.09% naphazoline/3% sodium chloride in eyes, and carry out the instillation (N=10) of placebo in other eyes.

Accompanying drawing 27 is bar charts, description be the average comfort level score that the sodium chloride ophthalmic preparation and the placebo of 0.09% naphazoline/3% had.

Accompanying drawing 28 is linear schedules, what describe is average globality eyelid swelled score, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: carry out the instillation of one 0.09% naphazoline/3% sodium chloride in eyes, and carry out the instillation of 0.05% oxymetazoline/3% sodium chloride in other eyes.(360 minutes) are estimated described eyelid swelled within 6 hours time.

Accompanying drawing 29 is linear schedules, what describe is average globality eyelid swelled score, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: carry out the instillation of one 0.09% naphazoline/7.5% glycerol in eyes, and carry out the instillation of 0.05% oxymetazoline/7.5% glycerol in other eyes.(360 minutes) are estimated described eyelid swelled within 6 hours time.

Accompanying drawing 30 is linear schedules, what describe is average globality eyelid swelled score, before wherein said eyelid swelled occurs in and instils (baseline) and just instiled after (time=0), wherein said instillation is: the instillation of 0.09% naphazoline/3% sodium chloride, the instillation of 0.05% oxymetazoline/3% sodium chloride, the instillation of 0.09% naphazoline/7.5% glycerol, the instillation of 0.05% oxymetazoline/7.5% glycerol.(360 minutes) are estimated described eyelid swelled within 6 hours time.

Accompanying drawing 31 is bar charts, what describe is the average comfort level score that following preparation is had and the comparison of carrying out: the sodium chloride of 0.09% naphazoline/3%, the sodium chloride of 0.05% oxymetazoline/3%, the glycerol of 0.09% naphazoline/7.5%, and the glycerol of 0.05% oxymetazoline/7.5%.

The specific embodiment

1. definition

For facility, before the present invention is further described, here some term that uses in described description, embodiment and accompanying Claim is collected.Those skilled in the art should read these definition and it is understood in the remainder content of described description.

The described term that is used in the present invention " acceptable comfort curve " refers to when when described eyes are used, the toleration that a kind of ophthalmic preparation had, wherein benefit from such ophthalmic preparation to described eyes that use is and can alleviates, comfort, treat and/or prevent a kind of vision disease, and this effect has surpassed by described preparation using and any uncomfortable danger that brings in described eyes, has for example increased the patient for the compliance monitoring of using described ophthalmic preparation in described eyes.

Described term " antiallergic reagent " refers to a kind of molecule or compositions for the treatment of optic hyperesthesia disease or alleviating the symptom of optic hyperesthesia disease.The example of antiallergic reagent comprises, but be not limited to, " hydryllin " or prevention histamine and described histamine receptor carry out bonded medicine, " mast cell stabilizers " or stop the medicine of the release and the release that other materials carry out of described histamine from described mastocyte, " medicine with multiple model of action " or antiallergic reagent medicine with multiple model of action are (for example, the medicine that belongs to antihistamine reagent and mast cell stabilizers, has antihistamine, the medicine of mastocyte stabilisation and anti-inflammatory activity, or the like), and non-steroid anti-inflammatory medicaments or " NSAID " and steroid.

What described term " aqueous " was generally speaking represented is a kind of waterborne compositions, and wherein water accounts for the weight greater than 50% in described carrier, be more preferably for greater than 75% weight and special in greater than 90% weight.

Described phrase " effective dose " is a term known in the art, and refer to a kind of dosage of reagent, when the reagent with this dosage imports in the pharmaceutical composition of the present invention, can can be applicable to any therapeutic treatment with a kind of rational benefit/risk than the effect that produces some expectation.In some embodiments, described term refers to and can eliminate, alleviate eyelid swelled or (for example keep, prevent its diffusion) necessary dosage or enough dosage, or can to eyelid swelled prevent or treat institute must multiple dose or enough dosage.Described effective dose may change according to following factor: described disease or the disease that need treat, the described particular composition that need use, the order of severity of perhaps described disease or disease.Those skilled in the art can by virtue of experience determine a kind of effective dose of particular agent, and needn't force it to carry out over-drastic test.For the treatment of described eyelid swelled, a kind of effective dosage preferably refers to a kind of dosage for the treatment of reagent, wherein said dosage can be with at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, perhaps at least 100% degree alleviates described eyelid swelled, the degree that alleviates of wherein said eyelid swelled is to utilize the lattice chi, the grade of the subjectivity of evaluation eyelid swelled (for example, but be not limited to, the clinical grade of subjectivity, described grade is determined as swelling slight, medium, serious, perhaps 0,1,2, perhaps 3, perhaps other grades that are fit to), and/or the 3D scanning technique measure.

Described term " eyelid swelled " refers to any nonallergic disease or the anaphylaxis disease that comprises described eyelid swelled or lid inflammation, comprises orbital edema.Such as, but be not limited to, the whole described disease that is listed in accompanying drawing 1 covered within the scope of described term nonallergic " eyelid swelled ".Therefore, defined in the present invention " eyelid swelled " contained the eyelid swelled of any reason, and its scope is from rare obstacle Blepharochalasis for example, and to common skin sagging disease comparatively, the feature of wherein said dermochalasis is " eye pouch ".Except these swelling are infected, also have many other anallergic diseases can cause the swelling of described eyelid, wherein said disease comprises, but be not limited to, lupus erythematosus, the dermatitis that causes by the medicine of cosmetics or local use, lymphoma, renal function imbalance and endocrine disturbance's (thyroid), and or even trichonematosis, described trichonematosis is a kind of infectious disease, and for this disease, described chronic edema near the eyes can be used as a kind of very effective diagnosis sign.The comparatively common reason of eyelid swelled comprises the age, the picked-up of ethanol, and tired and intraday variation (eyelid swelled in early morning) is read in the use of computer.The eyelid swelled in early morning occurs in and causes eyelid swelled in last night and the early morning when waking up.Further, optic hyperesthesia disease is one of modal reason of lid inflammation, and 20% influence that is subjected to this disease is nearly arranged among the whole crowd.In this case, the release that the mediator of the described molding in advance that takes place owing to the flailing action that is subjected to the mastocyte that IgE stimulates is arranged becomes clinical indication and the symptom that forms a kind of anaphylactic reaction, has caused the vasodilation of described vascular system and has made described liquid carry out seepage from described blood flow in described tissue.

The described term " hyperosmotic solution " that is used in the present invention refers to any solution with the weight infiltration molar concentration that is higher than another liquid, for example, comprise a kind of and any solution of other liquid phases than infiltrative active component with higher concentration.

The described term that is used in the present invention " optic hyperesthesia disease " refers to any anaphylactic disease of described eyes.The example of such optic hyperesthesia disease is including, but not limited to the seasonal/anaphylaxis conjunctivitis of property all the year round, vernal keratoconjunctivitis, huge nipple conjunctivitis, the anaphylaxis conjunctivitis of property and atopic keratoconjunctivitis all the year round.The sign and the symptom of described optic hyperesthesia disease comprise chemosis, and ophthalmic pruritus is furious, shed tears (tearing), and eyelid swelled.

Described term " infiltrative active agent " refers to a kind of hydrophilic reagent, for example, is a kind of reagent of hygroscopicity, hygroscopic reagent or other reagent, and described reagent can drive described seepage discharge in a kind of hyperosmotic solution.In order to possess infiltrative activity, the described weight infiltration molar concentration that a kind of solution had must be higher than the described weight infiltration molar concentration that its surrounding has.

Need to use method of the present invention can refer to human or inhuman animal, primates for example, mammal, and vertebrates to its " patient " who treats, " main body " or " host ".

Described phrase " the medicine acceptability " is known in the art and refers to such compositions, polymer and other materials and/or dosage form, they are present within the scope of rational medical judgment, be fit to use by the mode that contacts with described human tissue and animal tissue, and can not produce excessive toxicity, zest, anaphylactic reaction, perhaps other problems or complication have the rational benefit/risk ratio that matches.

Described phrase " the acceptable carrier of medicine " is known in the art, and refer to, for example, the material of medicine acceptability, compositions or solvent, for example a kind of liquid or solid filler, diluent, excipient, solvent or encapsulated substance, wherein the material of these medicine acceptabilities, compositions or solvent are partly to carry out the transmission of any fill-in or compositions or its component or transport the process involved to the another one of another organ or described body in a part from a kind of organ or described body.Each carrier must be " acceptability ", and its implication is that described carrier can be compatible with other compositions of described fill-in and be harmless for described patient.In some embodiments, a kind of carrier of medicine acceptability is non-pyrogen.Some examples that can be used as the material of the acceptable carrier of medicine comprise: (1) saccharide, lactose for example, glucose and sucrose; (2) starch based, for example corn starch and potato starch; (3) cellulose, and derivant, sodium carboxymethyl cellulose for example, ethyl cellulose and cellulose acetate; (4) Powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gel; (7) Talcum; (8) excipient, for example cupu oil and suppository wax; (9) oils, Oleum Arachidis hypogaeae semen for example, cotton seed oil, Oleum helianthi, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; (10) glycols, for example propylene glycol; (11) polyhydric alcohol, glycerol for example, sorbitol, mannitol and Polyethylene Glycol; (12) esters, for example ethyl oleate and ethyl laurate; (13) agar; (14) buffer reagent, for example magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) non-pyrogen water; (17) isobaric normal saline; (18) Luo Geshi solution; (19) ethanol; (20) phosphate buffered solution; (21) aqueous solution, suspension, ointment, and (22) other the non-toxicity tolerability material that can in pharmaceutical preparation, use.

Described term " salt of medicine acceptability " is known in the art, and refer to compositions of the present invention or the formed avirulent comparatively speaking inorganic acid addition salt of other any component and organic acid addition salt, including, but not limited to, therapeutic agent, excipient, other material and similar agents.The example of the acceptable salt of medicine comprises that those come from the salt of mineral acid, wherein said mineral acid is for example hydrochloric acid and sulphuric acid, and those come from the organic acid salt, wherein said organic acid is an ethane sulfonic acid for example, benzenesulfonic acid, o-toluene sulfonic acid, and similar organic acid.The example of the inorganic base that is fit to of preparation that is used for carrying out described salt is including, but not limited to hydroxide, carbonate and the bicarbonate of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and analogous element.Can use suitable organic base to form described salt equally, to such an extent as to comprise those avirulent and enough stable organic bases that can form this salt.In order to describe, the classification of such organic base can comprise monoalkylamine, dialkylamine, and trialkylamine, methyl amine for example, dimethyl amine, and triethylamine; The monohydroxy alkylamine, dihydroxy alkylamine or trihydroxy alkylamine be monoethanolamine for example, diethanolamine, and triethanolamine; Aminoacid, for example arginine and lysine; Guanidine; The N-methyl glucosamine; The N-methylglucosamine; L-glutaminate; N methyl piperazine; Morpholine; Ethylenediamine; N-benzyl phenethyl amine; (trihydroxy methyl) aminoethane; And similar organic base.Referring to, for example, the article of delivering among J.Pharm.Sci. " pharmaceutical science magazine " 66:1-19 (1977).

When relating to a kind of disease, the described term " prevention " that is used is known in the art, and refer to and carry out using of a kind of compositions, for the host who does not receive described compositions, the frequency of the symptom of using the medical conditions that can reduce the host of described compositions perhaps postpones the outbreak of symptom of described host's medical conditions.

Described term " treatment " is a term known in the art, it refers to by using one or more diagnostic reagents, treatment reagent or prevention reagent, thereby healing and/or alleviation that at least a symptom that any disease or disease had is carried out, wherein said diagnostic reagent, treatment reagent or prevention reagent are including, but not limited to for example infiltrative active agent of ophthalmology reagent, vasoconstrictor, convergence reagent, and the combination of mentioned reagent.

Described term " vasoconstrictor " refers to any medicine or the reagent that can shrink blood vessel, the reagent that plays a role on can α-1 receptor in being present in smooth muscle tissue.

2. eyelid swelled

Eyelid swelled may take place as the result of many different pathology diseases, and wherein said pathology disease comprises anaphylaxis, infects, slight stimulation/inflammation, wound, and the eyelid swelled in early morning.The eyelid swelled in early morning takes place as the result who organizes tonicity (lost tissue turgor) and inflammation who loses.Be accompanied by individual age growth, be present in described eyelid described skin on every side and lost its elasticity.With thinking that described corium provides rigidity and elastic collagen fiber to begin to decompose, this is a kind of natural process, over-drasticly be exposed under the sunlight or over-drastic being exposed under other destructive environmental stimuluses can be aggravated this natural process, wherein said destructive environmental stimulus is for example smoking.In addition, the orbital fat under it decomposes, and has caused having the formation of the tissue of lax, empty appearance again, has perhaps lost the tonicity of tissue.

When body one by one is being in when sleeping on the position of level, leak out the vascular system of liquid below described, enter in the structureless tissue in the cavity that is present in described around eyes and go, particularly enter into described palpebra inferior and go.This may be that accumulation owing to the inflammatory mediator causes, and wherein said inflammatory mediator is present among described tear film and the conjunctiva.The loss of elasticity of described corium makes described surperficial eyelid tissue expand along with the increase of liquid.When described individuality is waken up, described eyelid looks it is expansible and swelling, and this produces because be discharged into the excessive liquid that goes among the described eyelid tissue that has decomposed.The accumulation of different liquid may occur among the tissue that is positioned at described eye socket bone top, and the wherein said eye socket position of bone is on the tail of the eye of described palpebra inferior.This liquid may present the color of navy blue or purple, is the reason that causes occurring eye outward appearance tired, that have eye pouch.After individuality was waken up and presented a kind of upright position, because liquid has been discharged described eyelid tissue, eyelid swelled can weaken gradually.Yet such process may consume considerable time.

Eyelid swelled and periorbital edema are can distinguish mutually with the ocular edema of other types to come, and the ocular edema of wherein said other types is corneal edemas for example.As described, the formation of eyelid swelled be owing to liquid from described below vascular system seepage produce, wherein said vascular system is present within described eye socket zone and the socket of the eye week zone.Opposite is not contain blood vessel in the described cornea.Generally speaking corneal edema is caused by following reason: unusual intraocular pressure, electrolytical unbalance in the described corneal stroma, and/or the appearance of a kind of active metabolism pump in described endothelium, each in the said circumstances is all ordered about liquid and is flowed among the described cornea.

So, a kind of pharmaceutical composition that is formulated into to the purposes that can have the ophthalmology aspect is arranged, the active agent that comprises a kind of effective dose in the described compositions, wherein said active agent is selected from a kind of infiltrative active agent, a kind of vasoconstrictor, a kind of convergence reagent, or the combination of mentioned reagent, wherein said pharmaceutical composition directly is instilled in the eyes, thereby the mode of the vascular system by " draining (drying out) " described below is to occurring in seepage in described eyelid tissue and the socket of the eye week zone and treat and prevent, thereby effectively treats eyelid swelled.A kind of pharmaceutical composition that is formulated into to the purposes that can have the ophthalmology aspect is arranged, the active agent that comprises a kind of effective dose in the described compositions, wherein said active agent is selected from a kind of infiltrative active agent, a kind of vasoconstrictor, a kind of convergence reagent, or the combination of mentioned reagent, wherein said pharmaceutical composition is applied on the inner surface and/or outer surface of described ocular surface/eyelid, can effectively treat and prevent eyelid swelled equally.

3. pharmaceutical composition

The invention is characterized in the pharmaceutical composition that use new part, one or more that comprise effective dose in the wherein said pharmaceutical composition are present in the active agent within the carrier of medicine acceptability, in order to eyelid swelled and periorbital edema are treated and prevent.Described one or more active agents can include, but are not limited to, infiltrative active agent, vasoconstrictor, convergence reagent, or the combination of mentioned reagent.The effect of described convergence reagent or infiltrative active agent is to extract liquid out (accompanying drawing 2) from the tissue of the tissue of swelling or inflammation, and the effect of vasoconstrictor is to prevent that other liquid from leaking in the described eyelid tissue goes from the vascular system of described below.In a kind of specific embodiment, comprise at least two kinds of active agents in the pharmaceutical composition of the present invention, including, but not limited to infiltrative active agent, vasoconstrictor, convergence reagent, or the combination of mentioned reagent.

A kind of preferred embodiment in, pharmaceutical composition of the present invention is formulated into to having the weight infiltration molar concentration that 200 to 2000 millis permeate molar concentration/kilogram, preferably 250 millis permeate molar concentration/kilogram to 1500 millis and permeate molar concentration/kilogram, what be more preferably is that 260 millis permeate molar concentration/kilogram and permeate in the least molar concentration/kilogram to 1250, what be more preferably is that 265 millis permeate molar concentration/kilogram to 1200 millis and permeate molar concentration/kilogram, and what be more preferably is that 400 millis permeate molar concentration/kilogram and permeate in the least molar concentration/kilogram and what be more preferably is 500 to permeate molar concentration/kilogram in the least and permeate in the least molar concentration/kilogram to 1100 to 1150.When being instilled into such preparation in the eyes, it provides a kind of drop with acceptable comfort curve.

In one embodiment, described active agent is a kind of infiltrative active agent.In some embodiments, comprise a kind of hyperosmotic solution that contains infiltrative active agent in the described pharmaceutical composition.Compare with the electrolyte of being found in its surrounding, hyperosmotic solution contains the electrolyte of higher concentration.

In some embodiments, described infiltrative active agent is a kind of crystal osmotic agent.The example of crystal osmotic agent includes, but are not limited to, sodium chloride (NaCl), glucose, glycerol, mannitol, sorbitol, sucrose, state-promulgated pharmacopoeia level (NF) Polyethylene Glycol 3350, magnesium citrate and lactulose.

In some embodiments, described crystal osmotic agent is a mannitol.Mannitol is a kind of sugar alcohol form of mannose, its natural being present in many fruit and the vegetable.

In other embodiment, described crystal osmotic agent is a glycerol.Glycerol is that a kind of by-product as saponification obtains from fat and oily substance, and it is as a kind of solvent and be used among many ophthalmic products by frequent, and as a kind of component in the various different products and by frequent use, wherein said various product comprises cosmetics, soap, and lubricant.

In a kind of specific embodiment, described crystal osmotic agent is sodium chloride (solution, gel, suspension, the perhaps solvent of other medicine acceptability).In another specific embodiment, described crystal osmotic agent is glycerol (solution, gel, suspension, the perhaps solvent of other medicine acceptability).

In other embodiment, described crystal osmotic agent is a glucose.Glucose has gone through to be used for adult and pediatric patients are injected, as a kind of electrolyte, calorie and the source that is used to carry out the water of hydration.

In other embodiment, described crystal osmotic agent is state-promulgated pharmacopoeia level (NF) Polyethylene Glycol 3350.

In other embodiment, described crystal osmotic agent is a magnesium citrate.

In other embodiment, described crystal osmotic agent is a lactulose.Lactulose is a kind of synthetic sugar.

In some embodiments, described infiltrative active agent is a kind of colloid osmotic agent.The example of colloid osmotic agent comprises, but be not limited to, hetastarch (hetastarch), pentastarch (pentastarch), with the crosslinked gel polypeptide of carbamide, macrodex, Gentran 40, albumin, icodextrin, USP level (American Pharmacopeia rank) bentonite, NF level (state-promulgated pharmacopoeia level) aluminium magensium silicate 2A type (MgAlsilicate NF type 2A), NF level (state-promulgated pharmacopoeia level) alginic acid/sodium alginate, microcrystalline Cellulose and NF level (state-promulgated pharmacopoeia level) sodium carboxymethyl cellulose, carbomer and gellan gum.

In some embodiments, described colloid osmotic agent is hetastarch (hetastarch).Hetastarch is a kind of plasma expender, is used for the shock that the loss owing to liquid causes is treated.

In other embodiment, described colloid osmotic agent is pentastarch (pentastarch).Similar with hetastarch, pentastarch is a kind of plasma expender, is used for the shock that the loss owing to liquid causes is treated.

In other embodiment, described colloid osmotic agent is a kind of combination product of gel polypeptide, and wherein said gel polypeptide and carbamide have taken place crosslinked.

In other embodiment, described colloid osmotic agent is a macrodex.

In other embodiment, described colloid osmotic agent is a Gentran 40.Similar with macrodex, Gentran 40 is used to carry out substituting of liquid in shock.

In other embodiment, described colloid osmotic agent is an albumin.

In other embodiment, described colloid osmotic agent is an icodextrin.Icodextrin is a kind of derivant of sucrose, and it is as a kind of succedaneum of glucose, and by frequent use among infiltrative purposes.

In other embodiment, described colloid osmotic agent is NF level (state-promulgated pharmacopoeia level) aluminium magensium silicate 2A type (MgAl silicate NF type 2A).

In other embodiment, described colloid osmotic agent is an alginic acid.Alginic acid is a kind of tackifying resin that is separated from Sargassum, and can be used as a kind of osmotic agent.

In other embodiment, described colloid osmotic agent is the sodium carboxymethyl cellulose (CMC) of NF level (state-promulgated pharmacopoeia level).

In other embodiment, described colloid osmotic agent is a gellan gum.

In other embodiment, described colloid osmotic agent is a carbomer sodium.

In other embodiment, described colloid osmotic agent is a microcrystalline Cellulose.

There are basic difference in colloid and crystal on aspect their preparation.Crystal is added with electrolyte mainly based on a kind of aseptic aqueous solution in described aqueous solution.Crystal is present in the various preparation, is hypotonic preparation from those for blood plasma, to those isoosmotic or high reagent that oozes.Colloid is normally based on crystalloid solution, therefore contain water and electrolyte, but contain a kind of interpolation colloidal substance component (for example, a kind of particulate suspension, described granule has the diameter less than a millimicron, and described granule can not pass a kind of semipermeable membrane freely and spread).

Other the exemplary permeability active agent that uses in the pharmaceutical composition of the present invention be can be expected at and for example magnesium sulfate of chemical compound, magnesium chloride, lithium chloride comprised, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, calcium bicarbonate, sodium sulfate, calcium sulfate, acid potassium phosphate, calcium lactate, Magnesium succinate, the carbohydrate of tartaric acid and solubility is melitriose for example, glucose, caffeine, carbomer 934 P, tannic acid, ascorbic acid, glucosan-40000, inulin, menthol, polysorbate80, and the mixture of above-mentioned substance.In some embodiments, the effective dose of described osmotic agent is selected from the group of being made up of following dosage: about 0.001% caffeine to about 10% weight, about 0.001% carbomer 934 P to about 10% weight, about 0.001% tannic acid to about 10% weight, about 0.001% ascorbic acid to about 10% weight, about 0.001% glucosan-40000 to about 10% weight, about 0.001% inulin to about 10% weight, about 0.001% menthol to about 10% weight, about 0.001% Polyoxyethylene Sorbitan Monooleate, or the mixture of above-mentioned effective dose to about 10% weight.

In another embodiment, described active agent is a kind of convergence reagent (that is a kind of reagent that except that other aspects tissue is shunk).The example that can be expected at the convergence reagent that uses in the local pharmaceutical composition that uses of the present invention comprises, but be not limited to Radix Hamamelidis Mollis, zinc sulfate, silver sulfate, vegetable tannins acid, oak bark extract, five galloyl glucoses, Alumen, burow's solution (burow ' s solution), black brambles extract, european bird cherry extract and natural flavonoid.

In a kind of specific embodiment, described convergence reagent is Radix Hamamelidis Mollis.Radix Hamamelidis Mollis separates from a kind of herbaceous plant and obtains, described herbaceous plant be in Central Europe and southern Europe found.

In another specific embodiment, described convergence reagent is zinc sulfate.

In another specific embodiment, described convergence reagent is silver sulfate.

In another embodiment, described active agent is a kind of vasoconstrictor.In some embodiments, described vasoconstrictor is a kind of α-1 adrenaline excitant.In other embodiment, described vasoconstrictor is any reagent that can reduce the diameter of described blood vessel and therefore prevent seepage.Can be expected at α-1 adrenaline excitant that uses in the local pharmaceutical composition that uses of the present invention including, but not limited to naphazoline, oxymetazoline, phenylephrine, and tetrahydrozoline.In a kind of specific embodiment, can expect that the described vasoconstrictor that uses in the present invention is a naphazoline, and described effective dose about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, what be more preferably is 0.01% to about 0.5% weight/volume, even be more preferably for about 0.01% to about 0.2% weight/volume, even be more preferably for about 0.09% to about 0.1% weight/volume.In another specific embodiment, can expect that the described vasoconstrictor that uses in the present invention is an oxymetazoline, and described effective dose about 0.01% to the scope of about 0.2% weight/volume, what be more preferably is 0.01% to about 0.1% weight/volume, in addition be more preferably for about 0.03% to about 0.05% weight/volume.In another specific embodiment, can expect that the described vasoconstrictor that uses in the present invention is phenylephrine and described effective dose about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, what be more preferably is 0.01% to about 0.5% weight/volume, in addition be more preferably for about 0.05% to about 0.2% weight/volume.

In a certain embodiment, comprise a kind of vasoconstrictor and a kind of infiltrative active agent in the pharmaceutical composition of the present invention simultaneously.In a kind of specific embodiment, comprise naphazoline and sodium chloride in the pharmaceutical composition of the present invention simultaneously.In another specific embodiment, comprise oxymetazoline and sodium chloride in the pharmaceutical composition of the present invention simultaneously.In another specific embodiment, comprise naphazoline and glycerol in the pharmaceutical composition of the present invention simultaneously.In another specific embodiment, comprise oxymetazoline and glycerol in the pharmaceutical composition of the present invention simultaneously.Except other aspect, as described in the embodiment hereinafter, the outstanding effect that this preparation had is owing to the synergism that combination produced that is present in the described component among them.

The effective dose that may reside in a kind of active agent among the described compositions is to exist with about 0.001% dosage range to about 100.0% weight/volume.For example, the effective dose of described each active agent may reside in about 0.001% to the scope of about 0.01% weight/volume, about 0.01% to the scope of about 0.100% weight/volume, about 0.100% to the scope of about 1.0% weight/volume, about 1.00% to the scope of about 10.00% weight/volume, and perhaps about 10% to the scope of about 100% weight/volume.

Those of ordinary skills can recognize, the effective dose that is present in a kind of active agent among the preparation of the present invention will change according to the character that employed described active agent has, and change according to following factor, wherein said factor is including, but not limited to the absorption rate of described medicine, deactivation speed and discharge rate, the delivery rate of described chemical compound, and described one or more combination of agents.For example, the effective dose of sodium chloride is present in about 1% to the scope of about 10% weight/volume, and preferably about 1% to about 6% weight/volume, be more preferably for about 2% to about 5% weight/volume.The effective dose of glucose is present in about 1% to the scope of about 10% weight/volume, and preferably about 1% to about 6% weight/volume, be more preferably for about 2% to about 5% weight/volume.The effective dose of sucrose is present in about 1% to the scope of about 95% weight/volume, preferably about 10% to about 90% weight/volume, be more preferably for about 20% to about 80% weight/volume, even be more preferably for about 30% to about 70% weight/volume.The effective dose of glycerol is present in about 1% to the scope of about 30% weight/volume, preferably about 1% to about 20% weight/volume, be more preferably for about 1% to about 10% weight/volume, even be more preferably for about 5% to about 8% weight/volume.The effective dose of mannitol is present in about 1% to the scope of about 30% weight/volume, and preferably about 1% to about 20% weight/volume, be more preferably for about 10% to about 15% weight/volume.The effective dose of sorbitol is present in about 1% to the scope of about 100% weight/volume, preferably about 10% to about 90% weight/volume, be more preferably for about 20% to about 80% weight/volume, even be more preferably for about 30% to about 70% weight/volume.The effective dose of hetastarch (hetastarch) is present in about 1% to the scope of about 20% weight/volume, and preferably about 1% to about 10% weight/volume, be more preferably for about 4% to about 6% weight/volume.The effective dose of pentastarch (pentastarch) is present in about 1% to the scope of about 20% weight/volume, and preferably about 5% to about 15% weight/volume, be more preferably for about 5% to about 10% weight/volume.The effective dose of macrodex is present in about 1% to the scope of about 20% weight/volume, and preferably about 1% to about 10% weight/volume, be more preferably for about 4% to about 6% weight/volume.The effective dose of Gentran 40 is present in about 1% to the scope of about 20% weight/volume, and preferably about 1% to about 10% weight/volume, be more preferably for about 4% to about 6% weight/volume.Albuminous effective dose is present in about 10% to the scope of about 50% weight/volume, and preferably about 15% to about 30% weight/volume, and what be more preferably is about 20% albumin to about 30% weight/volume.

Can exist with the physical form that is fit to arbitrarily at the solid solute that exists with excessive level the most at the beginning, wherein said physical form is a microgranule for example, crystal, and bead, tablet, strip, membranaceous; Granule and similar form.

In some embodiments, another combination of agents that comprises one or more active agents and effective dose in the pharmaceutical composition of the present invention, wherein said one or more active agent is selected from a kind of osmotic agent, a kind of vasoconstrictor, and/or a kind of convergence reagent, described another reagent is for example a kind of other vasoconstrictor, tear substitute, antiallergic reagent, hydryllin, mast cell stabilizers, on-steroidal AID (NSAID), steroid, anti-inflammatory agent, antioxidation reagent, infection reagent, cholinomimetic energy reagent, or the combination of mentioned reagent.Described combination of agents can synergiticly play a role, thereby alleviates the swelling of eyelid.

Can be expected at the described exemplary vasoconstrictor that uses in the pharmaceutical composition of the present invention and include, but are not limited to, naphazoline, antolazine, tetrahydrozoline, oxymetazoline and phenylephrine.Except the swelling that alleviates eyelid, vasoconstrictor can also play a role as decongestant.In some embodiments, the effective dose of described vasoconstrictor is present in about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, be more preferably for about 0.01% to about 0.5% weight/volume, even be more preferably for about 0.01% to about 0.2% weight/volume.In a kind of specific embodiment, can expect that the described vasoconstrictor that uses in the present invention is a naphazoline, and described effective dose about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, what be more preferably is 0.01% to about 0.5% weight/volume, even be more preferably for about 0.01% to about 0.2% weight/volume, even be more preferably for about 0.09% to about 0.1% weight/volume.In another specific embodiment, can expect that the described vasoconstrictor that uses in the present invention is an oxymetazoline, and described effective dose about 0.01% to the scope of about 0.2% weight/volume, what be more preferably is 0.01% to about 0.1% weight/volume, in addition be more preferably for about 0.03% to about 0.05% weight/volume.In another specific embodiment, can expect that the described vasoconstrictor that uses in the present invention is phenylephrine and described effective dose about 0.01% to the scope of about 10% weight/volume, preferably about 0.01% to about 1% weight/volume, what be more preferably is 0.01% to about 0.5% weight/volume, in addition be more preferably for about 0.05% to about 0.2% weight/volume.

Various tear substitute is known in the art and can be used among the compositions of the present invention, described tear substitute including, but not limited to: polyhydric alcohol for example, glycerol, glycerol, Liquid Macrogol, PEG400, polysorbate80, propylene glycol, and ethylene glycol, polyvinyl alcohol, polyvidone, and polyvinylpyrrolidone; Cellulose derivative is hydroxypropyl emthylcellulose (being also referred to as hypromellose) for example, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, and methylcellulose; Glucosan is macrodex for example; The aqueous soluble protein example gel; Carbomer is carbomer 934 P for example, Carbopol 941, Acritamer 940 and carbomer 974P; And resin hydroxypropyl guar gum (HP-guar) for example.There are many such tear substitute to obtain by commercial the purchase, comprising, but be not limited to for example Bion of cellulose esters

Teargen Tears

Tears Naturale

TearsNaturale

And

And polyvinyl alcohol Akwa for example

Moisture

And

Tear substitute can be made up of paraffin equally, for example described can the acquisition by commercial the purchase Ointment.Other that are used as that tear substitute uses can commercially be bought the ointment that obtains and comprise Lubrifresh

Moisture Eyes

And Refresh

A kind of preferred embodiment in, described tear substitute, or one or more components wherein, be a kind of aqueous solution, the viscosity scope that described aqueous solution had makes fuzzy, eyelid caking or the like phenomenon is minimized.Preferably, described tear substitute or the viscosity that one or more components had wherein are within the scope of 30-150 centipoise (cpi), 30-130 centipoise preferably, be more preferably for the 50-120 centipoise, even be more preferably be 60-115 centipoise (or be present within the described scope any concrete value).In a kind of specific embodiment, described tear substitute or the viscosity that one or more components had wherein are about 70-90 centipoise, or are present in any concrete value within the described scope (such as, but be not limited to, 85 centipoises).

Can measure the viscosity that ophthalmic preparation of the present invention had according to standard method known in the art, wherein said standard method is for example to use viscometer or flow graph.Those of ordinary skills can recognize that for example the such factor of temperature and shear rate can influence the measured value of viscosity.In a kind of specific embodiment, under 20 ℃+/-1 ℃ condition, use the Bu Luokefei cone and plate viscometer (Brookfield Cone and PlateViscometer) of a kind of CP40 of having or cone of equal value that the viscosity that ophthalmic preparation of the present invention had is measured, the model of wherein said Bu Luokefei cone and plate viscometer is VDV-III Ultra ⁺It has about 22.50+/-shear rate of about 10 (1/ seconds), perhaps use the Bu Luokefei viscometer of a kind of SC4-18 of having or cone of equal value that the viscosity that ophthalmic preparation of the present invention had is measured, the model of wherein said Bu Luokefei viscometer is LVDV-E, its have about 26+/-shear rate of about 10 (1/ seconds).

In some embodiments, (for example use a kind of suitable salt, phosphate), described tear substitute or one or more components are wherein cushioned, make it have 5.0 to 9.0 pH, preferably have 5.5 to 8.5 pH, be more preferably and have 6 to 8 pH (or be present within the described scope any concrete value).In some embodiments, further comprise one or more compositions in the described tear substitute, including, but not limited to, glycerol, propylene glycol, glycine, sodium borate, magnesium chloride, and zinc chloride.

In the present invention a kind of preferred embodiment in, comprise hydroxypropyl emthylcellulose in the described tear substitute.For example, but be not limited to, a kind of tear substitute of hydroxypropyl emthylcellulose that comprises is

Profit eye drop.

(CibaVision-Novartis) be a kind of drop of aseptic lubricated eyes, wherein contain the hydroxypropyl emthylcellulose of 3 milligrams/gram and utilize Dexol to carry out anticorrosion.Other examples are provided at this based on hydroxypropyl emthylcellulose (HPMC) tear.

Another preferred embodiment in, comprise sodium carboxymethyl cellulose in the described tear substitute.For example, but be not limited to, the described described tear substitute of sodium carboxymethyl cellulose that comprises is

Tear.

Tear is a kind of and normal similar lubricant formulations of tear, wherein contains a kind of antiseptic---chlorine oxygen complex (Purite of stabilisation of non-sensibility of gentleness ^TM), described chlorine oxygen complex finally can change in use and become the component that exists in the natural tears.

Be suitable for use in exemplary on-steroidal AID (NSAID) among the compositions of the present invention including, but not limited to, amfenac, propanoic acid is naproxen for example, flurbiprofen, oxaprozin, ibuprofen, ketone ibuprofen, Fenoprofen; Ketorolac tromethamine

(and other chemical compounds with ophthalmology's effectiveness of in the U.S. Patent No. 4454151 of obtaining the authorization on June 12nd, 1984, describing at Waterbury, the relevant portion in the above-mentioned document is introduced into as a reference in the present invention); Acetic acid derivative is sulindac for example, indomethacin, and etodolac; Phenyl acetic acid is diclofenac for example

(and other chemical compounds with ophthalmology's effectiveness of in the U.S. Patent No. 4960799 of obtaining the authorization October 2 nineteen ninety, describing at Nagy, the relevant portion in the above-mentioned document is introduced into as a reference in the present invention), bromfenac, and suprofen; The aryl acetic acid prodrug is Nepafenac for example; Salicylic acid, aspirin for example, salicylic acid salicylic acid, diflunisal, Choline magnesium trisalicylate (CMT); The p-aminophenyl amphyl is acetaminophenol for example; Nabumetone class (naphthylalkanones) for example naphthalene fourth is closed ketone (nabumetone); The bmap acid derivant is piroxicam and meloxicam for example; Fragrant that hydrochlorate is mefenamic acid for example, meclofenamic acid salt and flufenamic acid; Pyrroles's acetic acid is tolmetin for example; And pyrazolone bute for example; Cycloxygenase-2 (COX-2) selective depressant is celecoxib for example, examines the west with cutting down, and Parecoxib is relied on and examined former times, and Luo Mei former times cloth; Comprise all esters of mentioned reagent and the salt of medicine acceptability.

Exemplary hydryllin includes, but are not limited to, pheniramine, antazoline, two fumaric acid emedastines, Ai Basiting, carebastine, levocabastine, cetirizine, and the salt of the medicine acceptability of mentioned reagent.

Exemplary mast cell stabilizers includes, but are not limited to, nedocromil, lodoxamide, pemirolast, cromoglicic acid, sodium cromoglicate, and the salt of the medicine acceptability of mentioned reagent.

Exemplary medicine with multiple model of action includes, but are not limited to, Azeptin, epinastine, olopatadine, ketotifen fumarate, bilastine, Bei Tuositing, the salt of the medicine acceptability of mizolastine and mentioned reagent.

One or more active agents in the described pharmaceutical composition can exist with the form of the salt of its medicine acceptability.

Described pharmaceutical composition can be formulated into in order to carry out the following form of local application: solution, suspension, oil, gel viscosity or quasi-viscous, emulsion, liposome, washing liquid, ointment, cream, gel, ointment, powder, and continue to discharge or the slow preparation that discharges, and the eyelid washing liquid, perhaps the solid composite of other types or semi-solid combination comprise the preparation that those are described in United States Patent (USP) 6808364.Described compositions can be carried out partial using with the form of spraying or the form of propellant equally.

Preferably, described pharmaceutical composition is a gel, discharges in order to one or more pharmaceutically active agents (for example, a kind of infiltrative active agent or a kind of vasoconstrictor, or the combination of mentioned reagent) carried out sustained release or to continue.Described preparation can be a kind of aqueous formulation that can carry out gelation in position.Comprise a kind of gelling reagent in such preparation, described gelling reagent is can promote effectively that the concentration of gelation exists, wherein said gelation is producing when coming in contact with eyes, or when with described external eyes in the generation when coming in contact of tear liquid.The gelling reagent that is fit to includes, but are not limited to, and thermosetting polymer is the quaternary ethylenediamine block copolymer of oxirane and expoxy propane (for example, protect beautiful look bright) for example; Polycarbophil; And polysaccharide gellan gum for example, carrageenan (for example, kappa-carrageenan and ζ-carrageenan), chitosan and alginate resin.

The described phrase that is used in the present invention " carries out gelation " and not only comprises those in position when coming in contact with eyes or can forming the low-viscosity liquid of having of gel with tear liquid in the described external eyes when coming in contact, comprise those liquid that more have viscosity for example semifluid and thixotropic gel equally, the wherein said liquid that more has viscosity can show the viscosity or the colloid hardness of remarkable increase on being applied to described eyes the time.Although it is preferred can showing such preparation of the further increase on viscosity or colloid hardness when using, if but described initial gel is enough to resist the effect of breaking up that the discharging owing to tear produces, thereby the concrete indicated effective remaining time of institute among the present invention can be provided, and then the above-mentioned character of described preparation is not the sin qua non's.

The ophthalmic preparation of lasting release with gel of high viscosity is described in U.S. Patent No. 4271143 and 4407792.Further, UK Patent Application GB 2007091A has described a kind of ophthalmic composition that exists with the form of gel, comprising a kind of aqueous solution of CVP Carbopol ETD2050, and a kind of water miscible alkaline matter and a kind of opthalmological.Can select, U.S. Patent No. 4615697 discloses a kind of compoistion and method of use of sustained release, and wherein said compositions is based on a kind of biological adhesive and a kind of reagent for the treatment of.

In some embodiments, can be formulated into form according to pharmaceutical composition of the present invention, in order to carry out partial using into hyperosmotic solution.Aqueous solution is easy to prepare, and can be easy to the patient is used by the mode to two described solution that instils in the described eyes that are subjected to affect.

The various arbitrarily carrier that can use in preparation of the present invention comprises water, water and can with the mixture of water-soluble mixed solvent, for example, but be not limited to, the C1-C7 alkanol comprises the vegetable oil or the mineral oil of 0.5% to 5% non-toxicity water-soluble polymer, natural product, example gel, alginate, pectin, tragacanth, the inferior natural gum of OK a karaoke club, xanthan gum, carrageenan, agar and Radix Acaciae senegalis, starch derivatives, for example acetic starch and hydroxypropyl starch, and other synthetic product, for example polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ethermaleic anhydride, poly(ethylene oxide), preferably crosslinked polyacrylic acid, for example neutral carbomer (Carbopol), or those mixture of polymers.Generally speaking the concentration that described carrier had be 1 times to 100000 times of concentration that described active component had.

Other the composition that can be included among the described preparation comprises tetanic property reinforcing agent, antiseptic, and solubilizing agent, non-toxic excipients, analgesics, chelating agen, the pH regulator agent, cosolvent and viscosity make up agent.

For described pH is regulated, preferably be adjusted to a kind of physiology pH, buffer agent is effective especially.The pH that described solution had should be maintained within 4.0 to 8.0 the scope, be more preferably for about 4.0 to 6.0, what be more preferably is about 6.5 to 7.8.The buffer agent that is fit to that can add is, for example, but be not limited to, boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, Tris (TRIS), and the mixture of various blended phosphate buffer (comprising the combination of sodium hydrogen phosphate, sodium dihydrogen phosphate and potassium dihydrogen phosphate) and mentioned reagent.Generally speaking, buffer agent will use with the dosage range that is present in about 0.05 to 2.5% weight, and preferred, is 0.1 to 1.5%.

If desired, generally speaking use tetanic property reinforcing agent that tetanic property is regulated.Such reagent is passable, for example be ion-type and/or nonionic.The example of the tetanic property reinforcing agent of ion-type is, but is not limited to, the halogenide of alkali metal or alkaline-earth metal, for example, calcium chloride, potassium bromide, potassium chloride, lithium chloride, sodium iodide, sodium bromide or sodium chloride, sodium sulfate or boric acid.The tetanic property reinforcing agent of nonionic is, for example, and carbamide, glycerol, sorbitol, mannitol, propylene glycol, perhaps glucose.In some embodiments, these reagent can be used as described active agent equally.In some embodiments, these reagent can be used to weight infiltration molar concentration is regulated equally.

In order to have infiltrative activity, the weight infiltration molar concentration that a kind of solution had must be higher than the weight infiltration molar concentration that its surrounding has.In common human eye, weight that described human tear film is had infiltration molar concentration is present within the scope that about 250-350 permeates molar concentration/kilogram (mOsm/Kg) in the least, permeate the meansigma methods of molar concentration/kilogram and in the individuality of suffering from the vision disease, can have up to about 450 millis, wherein said vision disease is including, but not limited to, dry eye disorders (its maximum surpasses 700 millis and permeates molar concentration/kilogram).Therefore, in order to bring into play therapeutic efficiency and to alleviate edema, bottom line must constrain in weight that a kind of ophthalmic solution had infiltration molar concentration on the weight infiltration molar concentration level that described people's ocular environment had (that is, about 250 to 450 millis permeate molar concentration/kilogram).Yet, be accompanied by the increase of weight infiltration molar concentration, when instiling, can produce the uncomfortable property of increase.High-caliber ion can activate teleneuron, and teleneuron can cause the vision twinge.Pass through comfort test, have been found that ophthalmic solution should have the weight infiltration molar concentration within the scope of permeating molar concentration/kilogram less than 2000 millis, and be more preferably less than 1050 millis and permeate molar concentration/kilogram, thereby have acceptable, i.e. the comfort curve of tolerability.Therefore, for a kind of for for the drop of preparing in order to the treatment of carrying out eyelid swelled, the scope of described target weight infiltration molar concentration is preferably permeated within molar concentration/kilogram at 200 to 2000 millis, being preferably 250 millis permeates molar concentration/kilogram and permeates in the least molar concentration/kilogram to 1500, be more preferably 260 millis and permeate molar concentration/kilogram to 1250 millis and permeate molar concentration/kilogram, be more preferably 265 millis and permeate molar concentration/kilogram to 1200 millis and permeate molar concentration/kilogram and be more preferably 400 and permeate in the least molar concentration/kilogram and permeate molar concentration/kilogram in the least and be more preferably 500 to 1150 and permeate molar concentration/kilogram in the least and permeate in the least molar concentration/kilogram to 1100.

In some embodiments, comprise a kind of antiseptic in addition in the described local preparation that uses.Generally speaking antiseptic can be selected from for example benzalkonium chloride (N-benzyl-N-(C of a kind of quaternary ammonium compounds ₈-C ₁₈Alkyl)-and N, N-dimethyl oronain), benzoxonium chloride or similar compounds.The examples of preservatives that is different from quaternary ammonium salt is the alkyl-mercury salt of thiosalicylic acid, for example, and thimerosal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate, Dexol, sodium chlorite, parabens, for example, methyl p-Hydroxybenzoate or propyl para-hydroxybenzoate, alcohols, for example, methaform, benzyl alcohol or phenylethanol, guanidine derivatives, for example, chlorhexidine or poly hexamethylene biguanide, Dexol

II or sorbic acid.Preferred antiseptic is a quaternary ammonium compounds, benzalkonium chloride or derivatives thereof Polyquad (referring to U.S. Patent No. 4407791) for example particularly, alkyl-mercury salt and p-Hydroxybenzoate.Under suitable opportunity, in described ophthalmic composition, add the antiseptic of enough dose, in use secondary pollution to be protected in order to guaranteeing, wherein said secondary pollution is caused by antibacterial and fungus.

In another embodiment, do not comprise antiseptic in the local preparation that uses of the present invention.Such preparation will be useful for those patients that worn contact lens, for those patients that used several local ophthalmology drops that use, will be useful perhaps, and/or (for example has dangerous ocular surface for those, xerophthalmia) patient will be useful, in described last a kind of situation, it may be more gratifying that restriction comes in contact with antiseptic.

The described local preparation that uses can need a kind of existence of solubilizing agent in addition, if particularly described active component or described non-active ingredient trend towards forming a kind of suspension or a kind of emulsion.Suitable solubilizing agent is for example to be selected from the group of being made up of following reagent place for above-mentioned relevant compositions: four fourth phenolic alcohol, the fatty acid glycerine polyvinyl alcohol ester, fatty acid polyvinyl alcohol ester, polyvinyl alcohol, glycerol ether, cyclodextrin (for example, alpha-cyclodextrin, beta-schardinger dextrin-or gamma-cyclodextrin, for example, alkylating derivant, the derivant of hydroxy alkylated, the derivant of carboxyalkylization or the derivant of alkoxy carbonyl alkylization, or monosaccharide groups alpha-cyclodextrin, monosaccharide groups beta-schardinger dextrin-or monosaccharide groups gamma-cyclodextrin, or diglycosyl alpha-cyclodextrin, diglycosyl beta-schardinger dextrin-or diglycosyl gamma-cyclodextrin, or single malt-base alpha-cyclodextrin, single malt-base beta-schardinger dextrin-or single malt-base gamma-cyclodextrin, or two malt-base alpha-cyclodextrin, two malt-base beta-schardinger dextrin-s or two malt-base gamma-cyclodextrins or panosyl-cyclodextrin), polysorbate20, the mixture of polysorbate80 or above-claimed cpd.An a kind of product that concrete example is a kind of Oleum Ricini and oxirane of particularly preferred solubilizing agent, for example described commercially available prod Cremophor

Perhaps Cremophor

The product that has confirmed Oleum Ricini and oxirane is outstanding especially solubilizing agent, and eyes have goodish toleration to described solubilizing agent.Another preferred solubilizing agent is selected from four fourth phenolic alcohol and cyclodextrin.The concentration that employed described concentration will depend on described active component especially and be had.Generally speaking, the described dosage that is added is enough to make described active component to dissolve.For example, the concentration that described solubilizing agent had is 0.1 times to 5000 times of the concentration that has of described active component.

Can further comprise atoxic excipient in the described preparation, for example, emulsifying agent, wetting agent or filler, for example, polyvinyl alcohol 200, polyvinyl alcohol 300, polyvinyl alcohol 400 and polyvinyl alcohol 600, perhaps Polyethylene Glycol (Carbowax) 1000, polyethylene glycol 1500, Macrogol 4000, polyethylene glycol 6000 and cetomacrogol 1000 0.Select the dosage and the kind of the excipient that added according to described particular demands, and generally speaking about 0.0001 to the scope of about 90% weight.

Can also in preparation of the present invention, add other chemical compound, in order to increase the viscosity of described carrier.The example that viscosity strengthens reagent includes, but are not limited to: polysaccharide, for example hyaluronic acid and salt thereof, chondroitin sulfate and salt thereof, glucosan, the various polymer of cellulose family; Polyvinyl; And acrylate copolymer.

4. using method

The invention is characterized in the method for in host, eyelid swelled being treated and preventing, comprising the above use of described described new preparation.For example, a kind of method for the treatment of eyelid swelled, described method comprises to described host's ocular surface uses a kind of pharmaceutical composition, comprises a kind of infiltrative active agent and/or a kind of vasoconstrictor and/or a kind of convergence reagent among the acceptable carrier of medicine of being present in of effective dose in the wherein said pharmaceutical composition.As the another one example, a kind of method for the treatment of eyelid swelled, described method may comprise to described host's outer eyelid surface and/or palpebra interna surface or ocular surface uses a kind of pharmaceutical composition, comprises a kind of infiltrative active agent and/or a kind of vasoconstrictor and/or a kind of convergence reagent among the acceptable carrier of medicine of being present in of effective dose in the wherein said pharmaceutical composition.In a kind of specific embodiment, may comprise in the method for described treatment eyelid swelled to described host's outer eyelid surface and/or palpebra interna surface or ocular surface and use a kind of pharmaceutical composition, comprise a kind of infiltrative active agent of effective dose and a kind of compositions of vasoconstrictor in the wherein said pharmaceutical composition.The various embodiment that is suitable for the such preparation among the method for the present invention is described above.

In various embodiment, described compositions can be used with following form: emulsion or suspension, liposome, washing liquid, ointment, cream, gel, ointment, perhaps powder, and the preparation that continues release or slowly discharge, and eyelid washing liquid, or the solid composite of other types or semi-solid combination, be included in the preparation of describing in the United States Patent (USP) 6806364.It can be used as a kind of eyes washing liquid equally or rinsing liquid uses, thereby eyes are carried out lavation.Described compositions can also be used with a kind of sprayable form.

The effective dose that is present in central described infiltrative active agent of described preparation and/or vasoconstrictor and/or convergence reagent will depend on absorption rate, deactivation speed and the discharge rate that described medicine has, and the delivery rate that comes from the described chemical compound in the described preparation.Comprise in a kind of embodiment of infiltrative active agent that at some described effective dose will depend on equally for described preparation being made the concentration of the described reagent that a kind of hyperosmotic solution needs.

The present invention provides a kind of scope of target capacity infiltration molar concentration and/or the scope of weight infiltration molar concentration for a kind of ophthalmic composition, in order to eyelid swelled is treated.Those skilled in the art should be easy to recognize, if the concentration that described compositions had is very low, this concentration that for example compositions of the present invention had, so described term capacity infiltration molar concentration and weight infiltration molar concentration be in itself equivalence and when they being applied in the compositions of the present invention, both can be used alternatingly in the present invention.Pass through comfort test, the present invention finds that ophthalmic solution should have capacity infiltration molar concentration and/or the weight infiltration molar concentration within the scope of permeating molar concentration/kilogram less than 2000 millis, and be more preferably less than 1050 millis and permeate molar concentration/kilogram, thereby have acceptable, i.e. the comfort curve of tolerability.Therefore, for a kind of for for the drop of preparing in order to the treatment of carrying out eyelid swelled, the scope of described target weight infiltration molar concentration is preferably permeated within molar concentration/kilogram at 200 to 2000 millis, being preferably 250 millis permeates molar concentration/kilogram and permeates in the least molar concentration/kilogram to 1500, be more preferably 260 millis and permeate molar concentration/kilogram to 1250 millis and permeate molar concentration/kilogram, be more preferably 265 millis and permeate molar concentration/kilogram to 1200 millis and permeate molar concentration/kilogram and be more preferably 400 and permeate in the least molar concentration/kilogram and permeate molar concentration/kilogram in the least and be more preferably 500 to 1150 and permeate molar concentration/kilogram in the least and permeate in the least molar concentration/kilogram to 1100.

What need note is, the order of severity of the described disease that the numerical value of dosage can be alleviated along with needs equally and changing.Need further be understood that, for any one specific host, should adjust concrete dosage along with the past of time, this adjustment is to finish according to the demand of described individuality and personnel's the professional judgement carrying out the application of described compositions or supervise the application of described compositions.Generally speaking, can use technology well known by persons skilled in the art that dosage is determined.

The dosage of any one chemical compound of the present invention will change according to following factor: the symptom that described patient had, age and other physical trait, the character and the order of severity of the described obstacle that need treat or prevent, the degree of the comfort level that expectation obtains, the described path of using, and the described form that provides.Described target formulation arbitrarily can be used with a kind of single dosage form, perhaps uses with separate dosage forms.Can utilize technology well known by persons skilled in the art or, be easy to determine the dosage of preparation of the present invention according to the instruction of being carried out among the present invention.

For any one specific formulation described in the present invention, need the effective dose or the amount of the described preparation of identification, and in any possible effect that is produced aspect the opportunity of using of described reagent.This can finish by routine test described in the present invention.Can estimate preparation had arbitrarily effectiveness and Therapeutic Method or effectiveness that prevention method had by following manner: thus use described preparation and use the effect that is produced and estimate described by measuring one or more indexs described in the present invention, effect that wherein said index and described reagent place have and described patient's comfort level degree are relevant, and these indexs numerical value of reaching after treatment is compared with the numerical value that same index reached before treatment, and perhaps the numerical value that these indexs are reached during a kind of different preparation of the numerical value that these indexs are reached after treating and use compares.

In a given patient, for the preparation of any specific, can producing, the opportunity of using reagent accurately and the dosage of effective therapeutic outcome will depend on following factor: the activity that described specific compound had, pharmacokinetics and bioavailability, described patient's physiological situation (comprises the age, sex, the type of disease and stage, general health, for a kind of given dosage and the responsiveness that medication therapy type had), the path of using, and similar factor.

The described guilding principle that provides among the present invention can be used to optimized processing is carried out in described treatment, for example, determine described best opportunity of using and/or dosage, this will only need to carry out routine test and get final product, and wherein said routine test is by described host being monitored and to described dosage and/or adjust two steps opportunity and form.

Can reduce dosage required for any individual components with being formulated into being used in combination that described several reagent place among the compositions of the present invention carry out, because the beginning of the effect that described different component had and time-continuing process are complementary.In such combined therapy, described various reagent can together be sent or is separated and be sent, and can send simultaneously or the different time within a day in send.

Can be by the mode that the change that eyelid swelled took place is measured, preparation of the present invention and compositions are estimated in the effect that is had aspect treatment and the prevention eyelid swelled, wherein said measurement can be used various method, including, but not limited to the grade of lattice chi measurement method, subjectivity (for example, but be not limited to, the clinical grade of subjectivity, described grade is determined as swelling slight, medium, serious, perhaps 0,1,2, perhaps 3, and/or the 3D scanning technique perhaps other grades that are fit to).A kind of preferred embodiment in, use the 3D scanning technique that the change that eyelid swelled took place is estimated.The use of 3D scanning technique can quantize fluctuation every day of eyelid swelled, this fluctuation is not carried out measuring accurately before, and what be used for the eyelid swelled that causes using various preparation of the present invention alleviates degree evaluation.

5. pack

Preparation described in the present invention can be packaged into and be a kind of product of single dose form or a kind of product of multiple dosage form.Before opening described packing, the product of described single dose form is aseptic, and is present in all components among the described packing and is intended to be consumed in the single application of carrying out in patient's eye or eyes.Opening after described packing is opened, generally speaking the aseptic of using a kind of antiseptic of antibiotic property to keep described compositions is unnecessary.

Before opening described packing, the product of multiple dosage form is aseptic equally.Yet, owing to be present in before whole components among the described container all are consumed, the described container that is used to hold described compositions may be opened many times, the product of described multiple dosage form must possess enough antibiotic property activity, thereby guarantee that described compositions can be by microbial contamination, wherein said microorganism is owing to repeating to open and handle to produce to described container carries out.Know to those skilled in the art for reaching the active level of the required antibiotic property of this purpose, and in the publication of official, concrete regulation is arranged, for example described American Pharmacopeia (" USP "), by other publications of Food and Drug Administration (the Food and Drug Administration) publication, and the corresponding publication of other countries.The detailed description of being carried out for the antiseptical concrete regulation of opthalmological product, and detailed description to carrying out in order to the operational approach of estimating the preservative efficacy that concrete preparation has, all in those publications, provide to some extent, wherein said anticorrosion at contamination by micro.In the U.S., generally speaking the preservative efficacy standard refers to described " USP PET " requires (described initial " PET " representative be " test of method effect ").

The use of the package arrangement of described single dose form, eliminated in described compositions demand for a kind of antimicrobial preservative, this is a significant advantage from medical science viewpoint aspect, because (for example be used for to ophthalmic composition, benzalkonium chloride) carries out antiseptical tradition antibacterial agent and can cause visual stimulus, particularly for suffering from xerophthalmia or having suffered from for the patient of visual stimulus.Yet, the package arrangement of current utilizable described single dose form has several shortcomings for manufacturer and consumer, the package arrangement of wherein said single dose form is the low capacity plastic bottle for preparing of the process by a kind of being called as " molding, fill and sealing " for example.The major defect that packaging system had of described single dose form is need quite a large amount of packaging material, have so not only wasted but also expensive, and have made troubles for described consumer.Same, have following risk: consumer is after carrying out the using of one or two in eyes, can as being instructed, they not do, abandon the container of described single dose form, but replace, with the compositions that keeps the above-mentioned container of having opened and be present in other any point, use later on.This inappropriate use that the product of single dose form is carried out has produced the danger that the product that makes described single dose form is subjected to microbial contamination, if and a kind of compositions of being polluted can produce the hazard that vision infects when being applied in the eyes.

Although the preparation described in the present invention preferably is formulated into the aqueous solution into " the instant use ", can anticipate that other reagent also is present within the scope of the present invention.Therefore, for example, other components in described active component, surfactant, salt, chelating reagent or the described ophthalmic solution or the mixture of said components, can be carried out lyophilizing or can be used as a kind of (for example can being dispersed in rapidly in the water, in the deionized water, perhaps in the distilled water) dry powder or tablet.Because the character of the self-preserving that described solution had, sterilized water is unwanted.

6. test kit

In another embodiment, the invention provides a kind of test kit, described test kit is used for preparation of the present invention is packed and/or stored and/or uses, and method of the present invention is implemented.Therefore, for example, test kit can comprise one or more container, and one or more ophthalmic preparations of the present invention, tablet or capsule are housed in the wherein said container.Can design described test kit, make it transportation, use and store one or more aspect in facilitate.

That can choose wantonly in the described test kit comprises guiding material, wherein contains the instruction (that is regulation) of the using method that the described preparation that provides in this test kit has been provided.Although generally speaking described guiding material comprises writing material or printing material, be not limited thereto.Can store these guidances and with any media that they are conveyed to the end user all be the present invention can expect.Such media includes, but are not limited to electronic storage medium (for example, disk, tape, chuck, chip), visual media (for example, CD ROM), and similar media).Can comprise the address of informing the position of the guiding material that provides such to the intern in such media.

Embodiment

The present invention has been carried out general description, with reference to following embodiment, can easierly understand the present invention, wherein said embodiment is only in order to be described some aspect of the present invention and embodiment in being included in, and is not intended in any manner and limits the invention.

Embodiment 1: the naphazoline ophthalmic solution of use 0.1% is to the blepharoedema in early morning The treatment of carrying out

In this research, the naphazoline ophthalmic solution to 0.1% is estimated in the effect that is had aspect the treatment blepharoedema.In the 1st day the afternoon 11 hosts' participating in the research eyelid volume is carried out record, and when arrive the clinic second day early morning (the 2nd day), again described eyelid volume is carried out record.All hosts have shown eyelid swelled in the morning the scanning when visiting for the second time increase.The natural process of the eyelid swelled in the early morning that use 3D scanning technique is measured is described in accompanying drawing 12.Described increase scope is from 14 cubic millimeters to 659 cubic millimeters.Afterwards, host's right eye is used 0.1% naphazoline (vasoconstrictor) and used the 3D scanner that described eyelid volume is estimated after 5 minutes, 10 minutes, 15 minutes, 30 minutes and 120 minutes of process treatment.Shown in accompanying drawing 3, in most host, two 0.1% naphazoline has caused reducing of eyelid swelled.When arriving described 30 minutes time point, compare with described untreated eyes, in 11 hosts, have nine hosts described through the eyes of treatment in (0.1% naphazoline) shown significantly the reducing of volume (accompanying drawing 3B-E, G-K).When arriving described 120 minutes time point, compare with described left eye, in 11 hosts, have 7 hosts in described right eye, shown significantly the reducing of volume (accompanying drawing 3B, C, E, G-I, K).Overview to all patient datas in accompanying drawing 3L is described.

In a word, these results have proved described 0.1% the effect that naphazoline had, it has the ability of the eyelid swelled that alleviates the patient, wherein said patient suffers from the eyelid swelled in early morning, described 0.1% naphazoline does not have the ability that alleviates the eyelid swelled in suffering from the eyes of disease, perhaps do not have the ability that alleviates the eyelid swelled in the vasodilative eyes of suffering from the fluid initiation, wherein suffer from the vasodilative eyes that fluid causes, generally speaking should use a kind of vasoconstrictor described.

Embodiment 2:: use a kind of colloid osmotic agent, 5% sodium chloride ophthalmic solution The treatment that the blepharoedema in early morning is carried out

Have in the preliminary study of similar design with described content above at one, 5% sodium chloride ophthalmic solution is as a kind of Therapeutic Method of blepharoedema of probability and be carried out evaluation.Two medicines have been carried out partial application and it has caused reduce (accompanying drawing 4) of eyelid swelled in several patients.After 5 minutes, 10 minutes, 15 minutes, 30 minutes and 120 minutes of process treatment, use the 3D scanner that described eyelid swelled is estimated.Three patients after through 15 fens clock times that instil, the reducing of the eyelid swelled of having demonstrated out.In a host, this reducing is significant and existence always in through the process of described 120 minutes evaluation time point.In described three remaining patients, treatment is invalid.

In a word, these results have proved that described 5% sodium chloride is in the effect to a certain degree that is had aspect the ability of the eyelid swelled that reduces some patient.The evaluation of carrying out for the meansigma methods that departs from baseline (accompanying drawing 4) shows that the treatment of sodium chloride is numerically seen and is better than negative control, although described difference does not have the significance on the statistical significance in this little research.

Further, with the independent component of the sodium chloride of 0.1% naphazoline and 5% comparatively speaking, 0.1% naphazoline and 5% sodium chloride carried out is combined in and reduces the eyelid swelled aspect and shown comparatively superior effect (accompanying drawing 5-7).

Embodiment 3: the sodium chloride ointment that uses 0.05% naphazoline/5% is to early morning The treatment that blepharoedema is carried out

In four (4) patients, the described naphcon that is dissolved in 0.05% in 5% the sodium chloride ophthalmology ointment is estimated in the effect that is had aspect the prevention eyelid swelled in early morning.Between the 4:30 to 5:30 in the afternoon, every eyes of every patient are carried out 3-D scanning.Every patient is required to take home a bottle that 5% sodium chloride ophthalmology ointment is housed, in described ophthalmology ointment, contain 0.05% naphcon, and require described patient before being about to sleep, described ointment to be applied in the described conjunctiva of right eye capsule.In second day early morning, between 7:30 to 8:00, each eye to the patient scan again.In result who scans in every patient's afternoon and the result who scans early morning, calculate with the average external volume in palpebra inferior zone in zone, described upper eyelid.Equally the difference that is present between the described meansigma methods is calculated.The result shows, described eyes through treatment are roughly half (accompanying drawings 8) of the swelling degree that has of described untreated eyes.

The final preparation that is used in this research is: be present in the sodium chloride of 5% in lanoline, mineral oil, pure water, the pure white vaseline, and 0.05% naphcon.

Embodiment 4: use sodium chloride (2.5%)/naphazoline (0.1%) and chlorination The treatment that sodium (5%)/naphazoline (0.1%) carries out the blepharoedema in early morning

By using the 3D scanning technique to measure, the compositions that naphazoline to 0.1% and 2.5% sodium chloride solution are formed is estimated treating and/or preventing the effect that is had aspect the eyelid swelled in early morning.

Utilize the sodium chloride of water preparation 2.5%.Afterwards naphazoline is dissolved in 2.5% the sodium chloride solution, thereby is mixed with 0.1% naphazoline concentration.

Estimate amounting to 6 hosts (male, the age is between 25 years old to 29 years old).In described research at first, use the 3D scanner every host and every eye to be carried out the baseline scan of five times (5).Second day, identical when visiting with the first time, require every eyes of host are carried out five times (5) scanning.

The host has accepted the treatment of two (every 40 microlitre) compositionss, and described treatment is carried out in eyes, has one minute interval between every, and described other eyes is not treated.Identical when visiting for the first time, after finishing 20 minutes of second instillation, every eyes are carried out five times (5) scanning.After through treatment, the host is required that the eyelid swelled to them of subjectivity carries out classification, and wherein said classification is (0 representative is the most comfortable, 10 represent the most uncomfortable) based on 0 to 10 comfort level.Take digital photos equally at the baseline place and after passing through 20 minutes that treat.

Is 3.3 just through the average comfort level level after instiling.For described right eye and left eye, the meansigma methods of the increase of eyelid volume in the morning the time is respectively 243 cubic millimeters and 309 cubic millimeters.For the eyes and untreated eyes of described process treatment, after 20 minutes of process treatment, the described value that on average reduces is respectively-100 cubic millimeters and-14 cubic millimeters.

These results show that the compositions of described 2.5% sodium chloride and 0.1% naphazoline can alleviate the eyelid swelled (accompanying drawing 9) in early morning really.Compare with the combination of 5% sodium chloride and 0.1% naphazoline, 2.5% sodium chloride has relatively poor effectiveness (be approximately its half) (referring to accompanying drawing 6 and accompanying drawing 9).This shows that sodium chloride is directly related with concentration in the effect that is had aspect the treatment eyelid swelled in early morning.

Aspect the comfort level level, described 2.5% sodium chloride is compared more comfortable with described 5% sodium chloride, and this is a kind of progress.In this research, described average comfort level level (3.3) is more more comfortable than the combination (5.8) of the naphazoline of described 5% sodium chloride/0.1%.

Embodiment 5: use 50% sucrose and naphazoline (0.1%) to early morning The treatment that blepharoedema is carried out

By using the 3D scanning technique to measure, the compositions that naphazoline (0.1%) and 50% sucrose solution are formed is estimated treating and/or preventing the effect that is had aspect the eyelid swelled in early morning.

Utilize water that sucrose is prepared, thereby form a kind of 50% concentration.Afterwards naphazoline is dissolved in the described sucrose solution, thereby is mixed with the concentration (0.1%) of naphazoline.

6 hosts estimate and method is similar to previous test to amounting to.In described research at first, use the 3D scanner every host and every eye to be carried out the baseline scan of five times (5).Second day, identical when visiting with the first time, require every eyes of host are carried out five times (5) scanning.

These results show that the preparation of the naphazoline of described 50% sucrose/0.1% can alleviate the eyelid swelled (accompanying drawing 10) in early morning really.Further, with the independent component of the naphazoline of 50% sucrose and 0.1% comparatively speaking, 50% sucrose and 0.1% the eyelid swelled aspect that reduces the patient that is combined in that naphazoline carried out have shown comparatively superior effect (accompanying drawing 11A and 11B).The average comfort level of described seminar is 5.2.

Embodiment 6: 0.25% the phenylephrine ointment that uses local application is to clearly The treatment that the blepharoedema in morning is carried out

By using the 3D scanning technique to measure, 0.25% phenylephrine ointment of local application is estimated treating and/or preventing the effect that is had aspect the eyelid swelled in early morning.

The host has accepted the treatment of two (every 40 microlitre) compositionss, and described treatment is carried out in eyes, has one minute interval between every, and described other eyes is not treated.Identical when visiting for the first time, after finishing 20 minutes of second instillation, every eyes are carried out five times (5) scanning.After through treatment, the host is required that the eyelid swelled to them of subjectivity carries out classification.Take digital photos equally at the baseline place and after passing through 20 minutes that treat.

These results show, 0.25% the phenylephrine ointment that carries out local application at described palpebra inferior place can alleviate the eyelid swelled (accompanying drawing 13) in early morning really.

Embodiment 7: use 12.5% the mannitol have 0.1% naphazoline and The treatment that 5% sodium chloride solution carries out the blepharoedema in early morning

By using the 3D scanning technique to measure, 12.5% the mannitol that has 0.1% naphazoline that is present among 5% the sodium chloride solution is estimated treating and/or preventing the effect that is had aspect the eyelid swelled in early morning.

These results show that the compositions of described mannitol/naphazoline/sodium chloride can alleviate the eyelid swelled (accompanying drawing 14) in early morning really.

Embodiment 8: the mannitol solution of use 12.5% carries out the blepharoedema in early morning Treatment

By using the 3D scanning technique to measure, the mannitol solution to 12.5% is estimated treating and/or preventing the effect that is had aspect the eyelid swelled in early morning.

The host has accepted the treatment of two (every 40 microlitre) compositionss, and described treatment is carried out in eyes, has one minute interval between every, and described other eyes is not treated.Identical when visiting for the first time, after finishing 20 minutes of second instillation, every eyes are carried out five times (5) scanning.

After through treatment, the host is required that the eyelid swelled to them of subjectivity carries out classification.Take digital photos equally at the baseline place and after passing through 20 minutes that treat.

These results show that described 12.5% mannitol solution can alleviate the eyelid swelled (accompanying drawing 15) in early morning really.

Accompanying drawing 16A and 16B have summarized the result that the described institute that is described is obtained in embodiment 1-8, and described with the independent eyelid swelled that is used for the treatment of early morning of described individual components and compared the more superior effect that described combination preparation had that is described among the embodiment 1-8.These results show, the described combination preparation that is described hereinbefore all is effectively alleviating aspect the eyelid swelled, and under most situation, compares with described independent part reagent, and described combination preparation provides a kind of synergism.

Embodiment 9: the sucrose solution of use 50% is to controlling that the blepharoedema in early morning is carried out Treat

By using the 3D scanning technique to measure, described sucrose (50%) is estimated treating and/or preventing the effect that is had aspect the eyelid swelled in early morning.

The host has accepted the treatment of two (every 40 microlitre) compositionss, and described treatment is carried out in eyes, has one minute interval between every, and described other eyes is not treated.Identical when visiting for the first time, after finishing 20 minutes of second instillation, every eyes are carried out five times (5) scanning.After through treatment, the host is required that equally the eyelid swelled to them of subjectivity carries out classification, and wherein said classification is (0 representative is the most comfortable, 10 represent the most uncomfortable) based on 0 to 10 comfort level.These results show that described 50% sucrose solution can MINly alleviate the eyelid swelled (accompanying drawing 17) in early morning.The average comfort level of described seminar is 4.5.

Embodiment 10: weight infiltration molar concentration and comfort level

The weight of being tried object is permeated the mutual relation that exists between molar concentration and the comfort level estimate, thereby determine relatedness, if present.The numerical value of corresponding weight infiltration molar concentration has been described in the described form shown in the accompanying drawing 18A, and just used every kind tried object instil after described average comfort level level (subjectivity grade based on 0 to 10,0 representative is the most comfortable, and 10 representatives are the most uncomfortable).

Do not wish to be subjected to the restriction of any theory, these results showed before weight infiltration molar concentration and comfort level and have a kind of direct relatedness that wherein, higher weight is permeated molar concentration can cause more intensive uncomfortable property (accompanying drawing 18B).Based on these data, it is contemplated that, under the prerequisite of the uncomfortable property that can not cause height, a kind ofly tried the maximum and ideal weight infiltration molar concentration that object has and permeated within the scope of molar concentration/kilogram less than 2000 millis, and preferably permeate within molar concentration/kilogram at 200 to 2000 millis, what be more preferably permeates molar concentration/kilogram at 250 millis and permeates within molar concentration/kilogram in the least to 1500, what be more preferably permeates molar concentration/kilogram to 1250 millis at 260 millis and permeates within molar concentration/kilogram, in addition be more preferably permeate in the least molar concentration/kilogram 265 and permeate within molar concentration/kilogram in the least to 1200.

Accompanying drawing 19 expression be the other comfort level numerical value that ophthalmic preparation had, wherein in described ophthalmic preparation, contain following combination: the combination of naphazoline (0.1% and 0.09%) and 3% sodium chloride; The combination of oxymetazoline (0.03%, 0.04%, 0.05%) and mannitol (12.5%, 6%, and 3%); 0.05% oxymetazoline, the combination of 6% mannitol and 3% sodium chloride; The combination of 0.05% oxymetazoline and 3% sodium chloride; And the combination of the glycerol of 0.05% oxymetazoline and 7.5%; And independent 0.05% oxymetazoline.Immediately the comfort level level was measured after just carrying out every kind of instillation that is tried object, wherein said measurement is according to previous description, based on the grade of the subjectivity of described 0-10.The weight that each had in described these preparations infiltration molar concentration is present within the target zone of the comfort curve that a kind of acceptability can be provided (that is, permeating molar concentration/kilogram at 500 millis permeates within the scope of molar concentration/kilogram to 1100 in the least) by prophesy.

Embodiment 11: use naphazoline (0.09%)/sodium chloride (3%) to early morning The treatment that blepharoedema is carried out

Design a kind of single center, double blinding, at random, intersection, placebo-controlled study, in order to estimate the described type that early morning, eyelid swelled was had when waking up every day, wherein said waking up occurs in the HOTEL FACILITIES and takes place in the family, continue 6 days altogether, and the sodium chloride ophthalmic solution of 0.09% naphazoline/3% of single dose form compared with placebo alleviating the effect that is had aspect the eyelid swelled in early morning estimate.

The sodium chloride ophthalmic solution of described 0.09% naphazoline/3% is to prepare according to the content shown in the form 1:

The sodium chloride ophthalmic solution of the naphazoline of form 1:0.09%/3%

Aimed quality (%)	Quality (mg/ml)	Raw-material description
			0.09	0.9	Naphcon, the American Pharmacopeia rank
3.0	30.0	Sodium chloride, the American Pharmacopeia rank
			0.1	1.0	Disodium edetate, the American Pharmacopeia rank
0.5	5.0	Boric acid, the state-promulgated pharmacopoeia level
			0.01	0.1	Benzalkonium chloride, the state-promulgated pharmacopoeia level

The hydrochloric acid that uses the sodium hydroxide of 0.5N or 0.5N with described pH regulator to 6.0 and use pure water (American Pharmacopeia level) (USP) with described preparation titration (QS) to 1 milliliter.

According to following content, to estimate amounting to 20 female host, the mean age of wherein said female host is 50 years old.In HOTEL FACILITIES, in (visit for the first time at night, night (pm)) and (visit for the second time when woke up morning in second day, baseline) screens (screening) and the baseline eyelid swelled is estimated, estimated as interval with ten minutes afterwards, carried out altogether one hour, wherein said evaluation is used be a kind of zonal/the eyelid swelled grade of globality.For eyelid swelled being carried out the evaluation of subjectivity, described eyelid and peripheral region are divided into four zoness of different of ocular, comprise described upper eyelid and palpebra inferior (being respectively zone 1 and zone 2) and be close to zone and the zone under the described palpebra inferior of next-door neighbour (being respectively zone 3 and zone 4) on the described upper eyelid.The host be required to each the zone in eyelid swelled carry out the scoring of subjectivity, with 0-3 as grade.The host is required for the basis eyelid swelled to be carried out the scoring of subjectivity with globality (that is, whole) equally.Use zero (" 0 ") must assign to represent described host in described evaluation region or with regard to globality, not detect any swelling; Use " 3 " must assign to represent described host in described evaluation region or with regard to globality, to detect clear and definite swelling.Accompanying drawing 20 invading the exterior show the average of each in four palpebral region described in the described base line measurement process when visiting and visiting for the second time for the first time.As represented in the accompanying drawing 20, in zone 3, detected maximum eyelid swelled, also be like this with regard to described globality.

After being visited the first time and the baseline evaluation carried out in visit for the second time, the host is returned to spends 6 days time in the family, for the host provides a diary, and require it at early morning of every day and night their eyelid swelled to be carried out the classification and the record of subjectivity, use therein is the eyelid swelled grade of described regionality/globality.

Show the meansigma methods of the globality score at the time point place of every day in described six day time at accompanying drawing 21 invading the exterior.As represented in the accompanying drawing 21, in the described whole six days time, compare with night the previous day, the experience that described host continues in the morning the increase of eyelid swelled.

Last described six day time, the host is back to the therapeutic test group (treatment arm) of described hotel as described research.In described HOTEL FACILITIES, again the eyelid swelled in night (visit for the third time) and early morning (the 4th visit) is carried out the evaluation of subjectivity, what wherein said evaluation was used is the eyelid swelled grade of previous described regionality/globality.After the eyelid swelled in the early morning to the 4th visit the time is estimated, make described host in eyes, accept the sodium chloride of one 0.09% naphazoline/3% immediately, and make in the described other eyes and accept Tears Naturale II artificial tears (placebo).After through treatment, use the eyelid swelled grade of described regionality/globality, as interval eyelid swelled was carried out the evaluation of 1 hour subjectivity with ten minutes, and use of improve the measurement that (that is, alleviate) carry out objectivity of digital photography art eyelid swelled.In order to carry out the measurement of described objectivity, be required described digital photos is estimated and evaluation is compared with baseline measures by the classification personnel (masked grader) of being concealed, whether described eyelid swelled obtains taking a turn for the better, worsens or does not change.In accompanying drawing 22-26, provided the described result that the subjectivity that carries out through the eyelid swelled after the treatment is estimated.

As represented among the accompanying drawing 22-26, in in described 4 specified palpebral region being estimated each, naphazoline/sodium chloride of 0.09% is alleviating aspect the eyelid swelled in early morning more effectively than placebo, also is like this with regard to described globality.

Equally the average comfort level of described treatment is estimated.After the sodium chloride that has carried out 0.09% naphazoline/3% instils, the host is required the comfort level that is present in the described drop among their eyes is carried out classification, wherein said classification utilization be with the subjectivity of 0-10 grade (0 the representative the most comfortable, 10 the representative the most uncomfortable).

Show described result at accompanying drawing 27 invading the exterior.As represented in the accompanying drawing 27, compare with placebo, described therapeutic test group (treatment arm) has 4.0 average comfort level score, and wherein said placebo is comparatively comfortable (average comfort level must be divided into 1.5).Weight that the sodium chloride ophthalmic solution of described 0.09% naphazoline/3% is had infiltration molar concentration is present within the target zone of the comfort curve that a kind of acceptability can be provided (that is, permeating molar concentration/kilogram at 500 millis permeates within the scope of molar concentration/kilogram to 1100 in the least) by prophesy.Have only three hosts after the sodium chloride that has carried out 0.09% naphazoline/3% in the eyes of accepting active treatment instils, reported of short duration zest.

In a word, after 40 minutes of process instillation, the eyes of the sodium chloride treatment of the naphazoline through 0.09%/3% all have the eyelid swelled score of reduction in all zones.Compare with placebo, all hosts have reported out identical globality score or better overall score (p value=0.001) for the eyes of described active treatment.The therapeutic effect of globality is alleviating of 0.4 unit.A kind of sodium chloride of 0.09% naphazoline/3% of dosage form is safe and is complete tolerability that it has 4.0 average comfort level score.Data in the diary show that in the described six days time, in described baseline HOTEL FACILITIES and treatment facility, the eyelid swelled in early morning is consistent with the type of the eyelid swelled at night.

Embodiment 12: naphazoline (0.09%)/sodium chloride (3%), 0.05% hydroxyl The glycerol of first azoles quinoline/3% sodium chloride, 0.09% naphazoline/7.5% and The treatment that the glycerol of 0.05% naphazoline/7.5% carries out the blepharoedema in early morning Comparison

Design a kind of monocentric crossing research, in order to the following preparation of single dose form is being alleviated that the effect that is had aspect the eyelid swelled in early morning is estimated and relatively: the sodium chloride ophthalmic solution of 0.09% naphazoline/3%, the sodium chloride ophthalmic solution of 0.05% oxymetazoline/3%, the glycerol ophthalmic solution of 0.09% naphazoline/7.5%, and the glycerol ophthalmic solution of 0.05% oxymetazoline/7.5%.

Described ophthalmic solution is to be prepared according to the indication among the form 2-5.

The sodium chloride ophthalmic solution of the naphazoline of form 2:0.09%/3%

Aimed quality (%)	Quality (mg/ml)	Raw-material description
			0.09	0.9	Naphcon, the American Pharmacopeia rank

3.0	30.0	Sodium chloride, the American Pharmacopeia rank
			0.1	1.0	Disodium edetate, the American Pharmacopeia rank
0.5	5.0	Boric acid, the state-promulgated pharmacopoeia level
			0.01	0.1	Benzalkonium chloride, the state-promulgated pharmacopoeia level

* weight is permeated molar concentration: 1030 millis permeate molar concentration/kilogram

The glycerol ophthalmic solution of the naphazoline of form 3:0.09%/7.5%

Aimed quality (%)	Quality (mg/ml)	Raw-material description
			0.09	0.9	Naphcon, the American Pharmacopeia rank
7.5	75.0	Glycerol, the American Pharmacopeia rank
			0.10	1.0	Disodium edetate, the American Pharmacopeia rank
0.5	5.0	Boric acid, the state-promulgated pharmacopoeia level
			0.01	0.1	Benzalkonium chloride, the state-promulgated pharmacopoeia level

* weight is permeated molar concentration: 938 millis permeate molar concentration/kilogram

The sodium chloride ophthalmic solution of the oxymetazoline of form 4:0.05%/3%

Aimed quality (%)	Quality (mg/ml)	Raw-material description
			0.05	0.5	Oxymetazoline hydrochloride, the American Pharmacopeia rank
3.0	30.0	Sodium chloride, the American Pharmacopeia rank
			0.1	1.0	Disodium edetate, the American Pharmacopeia rank
0.5	5.0	Boric acid, the state-promulgated pharmacopoeia level
			0.01	0.1	Benzalkonium chloride, the state-promulgated pharmacopoeia level

* weight is permeated molar concentration: 1027 millis permeate molar concentration/kilogram

The glycerol ophthalmic solution of the oxymetazoline of form 5:0.05%/7.5%

Aimed quality (%)	Quality (mg/ml)	Raw-material description
			0.05	0.5	Oxymetazoline hydrochloride, the American Pharmacopeia rank
7.5	75.0	Glycerol, the American Pharmacopeia rank
			0.1	1.0	Disodium edetate, the American Pharmacopeia rank
0.50	5.0	Boric acid, the state-promulgated pharmacopoeia level
			0.01	0.1	Benzalkonium chloride, the state-promulgated pharmacopoeia level

* weight is permeated molar concentration: 937 millis permeate molar concentration/kilogram

For in the above-mentioned preparation each, the hydrochloric acid that uses the sodium hydroxide of 0.5N or 0.5N is its pH regulator to 6.0, and use pure water (American Pharmacopeia level) (USP) with each preparation titration (QS) to 1 milliliter.

Similar with the described research of describing among the embodiment 11, this research is finished in HOTEL FACILITIES.At night described host is screened (screened) and eyelid swelled carried out the evaluation of subjectivity.Baseline eyelid swelled to early morning is estimated immediately when waking up, and what wherein said evaluation was used is the eyelid swelled grade of the previous described globality that is described in embodiment 11.After the baseline measures in early morning was estimated, medicine immediately in the following manner instiled in every host's eyes.11 hosts have accepted naphazoline/sodium chloride ophthalmic solution of one 0.09% in eyes, and have accepted oxymetazoline/sodium chloride solution of one 0.05% in described other eyes.Make other 11 hosts in eyes, accept the glycerol of one 0.09% naphazoline/7.5%, and in described other eyes, accepted the glycerol of one 0.05% oxymetazoline/7.5%.In through first hour after the above-mentioned processing, used the eyelid swelled grade of described globality that eyelid swelled is estimated with 20 minutes as interval, afterwards, in through the second hour after handling, estimated as interval with 30 minutes, subsequently, estimate as interval with 1 hour, during after arriving treatment 6 hours.

Show described result at accompanying drawing 28-31 invading the exterior.As represented in the accompanying drawing 28, in through 6 hours interval after the treatment, the sodium chloride of the sodium chloride of 0.09% naphazoline/3% and 0.05% oxymetazoline/3% all is effective alleviating aspect the eyelid swelled in early morning.The sodium chloride of 0.05% oxymetazoline/3% has the better slightly degree that alleviates in the eyelid swelled of globality aspect alleviating.Yet, when selecting between the sodium chloride of oxymetazoline/3% of the sodium chloride that requires naphazoline/3% 0.09% and 0.05%, they are more prone to the sodium chloride solution of described 0.09% naphazoline/3% to have accepted to have among the host of two kinds of treatments 66.6% expression at the same time.

As represented in the accompanying drawing 29, in through 6 hours interval after the treatment, the glycerol of the glycerol of 0.09% naphazoline/7.5% and 0.05% oxymetazoline/7.5% all is that effectively the glycerol of 0.09% naphazoline/7.5% has the better slightly degree that alleviates alleviating aspect the eyelid swelled in early morning.When requiring to select between described two kinds of ophthalmic solution, 66.6% expression is arranged in described host, and they are more prone to the glycerol solution of described 0.09% naphazoline/7.5%.

Accompanying drawing 30 expression be for whole 4 kinds of ophthalmic solution of above-mentioned acceptance test in the comparison that alleviates the effect that is had aspect the eyelid swelled in early morning (in order to compare, different treatment groups has been carried out normalize, wherein said normalize is based on identical baseline (that is, before the instillation of carrying out drop) value and carries out).As represented in the accompanying drawing 30, described solution based on 7.5% glycerol (promptly, the glycerol of the glycerol of 0.09% naphazoline/7.5% and 0.05% oxymetazoline/7.5%) (promptly than described solution based on 3% sodium chloride, the sodium chloride of the sodium chloride of 0.09% naphazoline/3% and 0.05% oxymetazoline/3%) more effective, this is wonderful and is not reckon with.Those skilled in the art can expect: sodium chloride, a kind of have higher tetanic reagent than glycerol, should be more efficiently alleviating aspect the eyelid swelled in early morning.Yet described result shows that described solution based on glycerol is more efficiently.

The host is required the comfort level that is present in the described drop among their eyes is carried out classification equally, wherein said classification utilization be grade (0 representative is the most comfortable, and 10 representatives are the most uncomfortable) with the subjectivity of 0-10.Show described result at accompanying drawing 31 invading the exterior.As represented in the accompanying drawing 31, have been found that described ophthalmic solution based on 7.5% glycerol is more more comfortable than described ophthalmic solution based on 3% sodium chloride, although described based on 7.5% glycerol solution and all be present in based in the solution of 3% sodium chloride each within the scope of target weight infiltration molar concentration of the described comfort curve that a kind of acceptability can be provided.Five hosts are arranged after the instillation of having accepted described solution based on sodium chloride, reported zest/burn feeling.

In a word, described solution based on 7.5% glycerol (promptly, the glycerol of the glycerol of 0.09% naphazoline/7.5% and 0.05% oxymetazoline/7.5%) be more efficiently alleviating aspect the eyelid swelled in early morning, can be better and reduce from the eyelid swelled measured value of baseline faster.In addition, have been found that described solution based on glycerol is more comfortable, without any the report of side effect.In described preparation through test, although the glycerol of described 0.09% naphazoline/7.5% numerically shows in a little more effectively character that is had aspect the eyelid swelled in the early morning that alleviates globality, described difference is not remarkable.Same find that the glycerol solution of described 0.09% naphazoline/7.5% is more comfortable, and compare, more be subjected to host's favor with the glycerol solution of described 0.05% oxymetazoline/7.5%.

The glycerol ophthalmic solution of the oxymetazoline of embodiment 13:0.05%/7.5% is to early morning The treatment carried out of blepharoedema

Design a kind of monocentric crossing research, in order to the effect that is had aspect the eyelid swelled in early morning is estimated and relatively, wherein said research is finished under the HOTEL FACILITIES condition alleviating to the glycerol ophthalmic solution of 0.05% oxymetazoline/7.5% of single dose form.

In the time in about 1 week, carry out four visits.In the process of visit for the first time,, use the regionality/globality eyelid swelled grade of described subjectivity and score system and digital photos that the baseline eyelid swelled at night is estimated according to the description of carrying out among the embodiment 1.In addition, in the afternoon 6 to 9 time of afternoon, with one hour as interval, researcher is estimated for the rubescent grade of eyes.

In the process of visit for the second time, use the regionality/globality eyelid swelled grade of described subjectivity and score system and digital photos that the baseline eyelid swelled in early morning is estimated.When after waking up 20 minutes, 40 minutes and 60 minutes, researcher is estimated the rubescent grade of eyes equally immediately, afterwards, in the 6 hour time after waking up, per hour the rubescent grade of eyes is estimated.

In the process of visit for the third time, identical program was estimated the eyelid swelled and the rubescent degree of eyes at night when use was visited with the first time.

In the process of the 4th visit, the eyelid swelled in early morning is estimated according to the described program of when visiting for the second time, using.Afterwards, patient's quilt therapeutic test group (treatment arm) that assigns at random, and in eyes, accept 1 research medicine.

After instiling, according to estimating on research evaluation method and opportunity identical when visiting for the second time.According to before described (grade of 0-10,0 the representative comparatively comfortable, 10 the representative comparatively uncomfortable), equally the comfort level that described preparation had is carried out the evaluation of subjectivity.

Described therapeutic test group (treatment arm) is as follows:

The oxymetazoline ophthalmic solution of preparation 1:0.05%

The glycerol ophthalmic solution of the oxymetazoline of preparation 2:0.05%/7.5%

Preparation 3: the solvent in the preparation 1 (do not contain oxymetazoline, do not contain glycerol)

Preparation 4: the solvent in the preparation 2 (7.5% glycerol does not contain oxymetazoline)

The same 3D scanning technique of using is alleviating that the effect that is had aspect the eyelid swelled in early morning is estimated and relatively to these four kinds of preparations.Before treating,, use the 3D scanner that every host and every eyes are carried out the scanning of baseline in the early morning of described night and next day.Afterwards, patient's quilt therapeutic test group (treatment arm) that assigns at random, and in eyes, accept 1 research medicine.Through after instiling, in the interval of routine, immediately every eyes are carried out 3D scanning.

Embodiment 14: the osmotic agent/vasoconstriction agent formulation of new combination is to the eye in early morning The treatment that blepharedema is carried out

The following chemical reagent that in vitro adds about 0.5 gram to each polypropylene of 50 milliliters.Above-mentioned operation is repeated once.

1. caffeine

2. carbomer 934 P

3. tannic acid

4. ascorbic acid

5. Gentran 40 000

6. inulin

7. mannitol

8. menthol (0.05 gram)

9. menthol (0.05 gram), polysorbate80 (0.50 gram)

In test tube 1-9 each in vitro adds 50 milliliters oxymetazoline hydrochloride sample and carries out eddy current and stir.In vitro add 50 milliliters naphcon sample and carry out the eddy current stirring to remaining 9.Each solution is carried out the test of pH and weight infiltration molar concentration.Provided described result in the form 6 below.

Form 6: the pH of various eyelid swelled preparation and weight infiltration molar concentration

Sample	pH	Weight infiltration molar concentration (milli permeates molar concentration/kilogram)
			BCL393-028-1A naphazoline/caffeine	5.99	?1035

BCL393-028-1B naphazoline/carbomer 934 P*	6.08
			BCL393-028-1C naphazoline/tannic acid	5.98	1038
BCL393-028-1D naphazoline/ascorbic acid	6.02	1098
			BCL393-028-1E naphazoline/Gentran 40 000	5.94	1005
BCL393-028-1F naphazoline/inulin	5.90	1011
			BCL393-028-1G naphazoline/mannitol	5.97	1095
BCL393-028-1H naphazoline/menthol	5.98	1011
			BCL393-028-1I naphazoline/menthol, polysorbate80	6.00	1005
Sample	pH	Weight infiltration molar concentration (milli permeates molar concentration/kilogram)
			BCL393-028-2A oxymetazoline/caffeine	6.07	?948
BCL393-028-2B oxymetazoline/carbomer 934 P	6.06
			BCL393-028-2C oxymetazoline/tannic acid	5.97	?954
BCL393-028-2D oxymetazoline/ascorbic acid	6.00	?1029

BCL393-028-2E oxymetazoline/Gentran 40 000	6.03	?927
			BCL393-028-2F oxymetazoline/inulin	6.03	?957
BCL393-028-2G oxymetazoline/mannitol	5.95	?1023
			BCL393-028-2H oxymetazoline/menthol	5.97	?1035
BCL393-028-2I oxymetazoline/menthol, polysorbate80	5.98	?1035

* note: when attempting to carry out the adjusting of pH, solution becomes gel form.

According to the description of carrying out among the embodiment 1-9 above, use the 3D scanning technique that in the above-mentioned preparation each is tested alleviating the effect that is had aspect the eyelid swelled in early morning, and according to the description of carrying out among the embodiment 11 and 12 above, use the regionality/globality eyelid swelled grade and the score system of described subjectivity, in the above-mentioned preparation each is tested alleviating the effect that is had aspect the eyelid swelled in early morning.According to before described (grade of 0-10,0 the representative comparatively comfortable, 10 the representative comparatively uncomfortable), equally the comfort level that described preparation had is carried out the evaluation of subjectivity.

Equivalents

The ophthalmic preparation of the part use that is used for the treatment of eyelid swelled is provided in a part of content of the present invention.Although the specific embodiment of the present invention is discussed, above-mentioned description is descriptive and is not restrictive.When this description is looked back, many distortion of the present invention will be conspicuous to those skilled in the art.Described accompanying Claim also is not intended to and asks for protection all these embodiments and distortion thereof; by with reference to described claim, together with they the full breadth of equivalents and described description, together with such distortion, should determine the complete scope that the present invention has.

Mentioned in the present invention all publications and patent, be included in those projects of hereinafter listing, all be introduced in the present invention as a reference as a whole, just indicated especially and divide other to indicate and be introduced into as a reference as the independent publication of each piece or patent.If situation about falling into contradictions, comprises in this application any definition of record at the application, will occupy an leading position.

List of references:

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Beltrani VS.2001.Eyelid dermatitis.Curr Allergy Asthma Rep.1:380-388.[0113] Zide BM and Jelks GW.1985.The eyelids.Chapter 3, pp.21-32, in Surgical Anatomy of the Orbit.Raven, the article " eyelid dermatitis " that New York.Beltrani VS delivered in " the general report of anaphylaxis and asthma " 1:380-388 in calendar year 2001.[0113] article " eyelid " in " surgical anatomy of eye socket " the 3rd chapter 21-32 page or leaf, delivered in 1985 of Zide BM and JelksGW, Raven publishing house, New York.

Wobig is anatomy.Chapter 7 J.1982.Eyelid, pp.78-87, inCosmetic Oculoplastic Surgery, Putterman AM, ed.Grune﹠amp; Stratton, the article " eyelid anatomy " that New York.Wobig J delivered in " cosmetic eye plastic operation " the 7th chapter 78-87 page or leaf in nineteen eighty-two, Putterman AM edits.Grune﹠amp; Stratton, New York.

Langley KE, Patrinely JR, Anderson RL, and Thiese SM.1987.Unilateral blepharochalasis.Ophthalmic Surg.18:594-598.LangleyKE, Patrinely JR, Anderson RL, and the article " one-sided Blepharochalasis " in " ophthalmic surgery " 18:594-598, delivered in 1987 of Thiese SM.

American Society for Aesthetic Plastic Surgery (ASAPS) .Newrelease:March 4,2003.Available at: Http: //www.surgery.org/news releases/mar0303stats.html.U.S. plastic surgery association (ASAPS) is in the article of new issue on March 4th, 2003.Can Http: //www.surgery.org/news releases/mar0303stats.html.The place obtains.

The article " hyperosmotic solution in glaucoma " that Kolker AE.1970.Hyperosmotic solutions in glaucoma.Investigative Ophthalmology.9:418-423.Kolker AE delivered in " research property ophthalmology " 9:418-423 in 1970.

Bielory?L.2000.Allergic?and?immunologic?disorders?of?theeyes.Part?II：Ocular?allergy。Article " allergic disorders of eyes and the immunity obstacle " second portion that J Allergy Clin Immunol.106:1019-1032.Bielory L delivered in " hypersensitive clinical immune magazine " 106:1019-1032 in 2000: optic hyperesthesia disease.

The article " eyelid swelled and pain: the research of a Chinese herbal medicine case " that Carter BB.1999.Eye swelling and pain:a Chinese herbal casestudy.www.pulsemed.org.Carter BB delivered in 1999.www.pulsemed.org.

Greiner JV, Peace DG, Baird RS, and Allansmith MR.1985.Effects of eye rubbing on the conjunctiva as a model of ocularinflammation.Am J Ophthalmol.100:45-50.Greiner JV, PeaceDG, Baird RS, and the article ", rubbing one's eyes " in " U.S. ophthalmology magazine " 100:45-50, delivered in 1985 of Allansmith MR to the influence of conjunctiva as a kind of model of eye inflammation.

The article " a kind of initial form of expression of lupus erythematosus: periorbital edema " that Chen DM and Crosby DL.1997.Periorbital edema as an initialpresentation of rosacea.J Am Acad Dermatol.37:346-348.ChenDM and Crosby DL delivered in " U.S. dermatological association magazine " 37:346-348 in 1997.

Smith NH, Rados WT, Cohen FB, and Cinotti AA.1997.Malignant lymphoma presenting as bilateral swelling of the eyelid.JMed Soc NJ.74:968-970.[0123] Jacobson DM.2000.Dysthyroidorbitopathy.Semin Neurol.20:43-54.Smith NH, Rados WT, CohenFB, and the article in " New Jersey medical association magazine " 74:968-970, delivered in 1997 of Cinotti AA " malignant lymphoma presents as a kind of bilateral swelling of eyelid ".[0123] article " thyroid orbital disease " in " neurological symposium " 20:43-54, delivered in 2000 of Jacobson DM.

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Claims

1. local pharmaceutical composition that uses, be used in host, eyelid swelled being treated and preventing, comprise a kind of carrier of medicine acceptability and a kind of infiltrative active agent and a kind of vasoconstrictor of effective dose in the wherein said pharmaceutical composition, the sodium chloride that wherein said infiltrative active agent is 3% weight/volume or the glycerol of 7.5% weight/volume, and vasoconstrictor is the naphazoline of 0.09% weight/volume or the oxymetazoline of 0.05% weight/volume.

2. according to the compositions described in the claim 1, wherein said osmotic agent is that the glycerol and the described vasoconstrictor of 7.5% weight/volume is the naphazoline of 0.09% weight/volume.

3. according to the compositions described in the claim 1, wherein said osmotic agent is that the glycerol and the described vasoconstrictor of 7.5% weight/volume is the oxymetazoline of 0.05% weight/volume.

4. according to the compositions described in the claim 1, wherein said osmotic agent is that the sodium chloride and the described vasoconstrictor of 3% weight/volume is the naphazoline of 0.09% weight/volume.

5. according to the compositions described in the claim 1, wherein said osmotic agent is that the sodium chloride and the described vasoconstrictor of 3% weight/volume is the oxymetazoline of 0.05% weight/volume.

6. according to the compositions described in the claim 1, the weight infiltration molar concentration that wherein said compositions had is permeated molar concentration/kilogram to 1050 millis at 500 millis and is permeated between molar concentration/kilogram.

7. local pharmaceutical composition that uses, be used in host, eyelid swelled being treated and preventing, comprise a kind of carrier of medicine acceptability and the naphcon of 0.9 mg/ml in the wherein said pharmaceutical composition, the sodium chloride of 30 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions are 6.0.

8. local pharmaceutical composition that uses, be used in host, eyelid swelled being treated and preventing, comprise a kind of carrier of medicine acceptability and the naphcon of 0.9 mg/ml in the wherein said pharmaceutical composition, the glycerol of 75 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions are 6.0.

9. local pharmaceutical composition that uses, be used in host, eyelid swelled being treated and preventing, comprise a kind of carrier of medicine acceptability and the oxymetazoline hydrochloride of 0.5 mg/ml in the wherein said pharmaceutical composition, the sodium chloride of 30 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions are 6.0.

10. local pharmaceutical composition that uses, be used in host, eyelid swelled being treated and preventing, comprise a kind of carrier of medicine acceptability and the oxymetazoline hydrochloride of 0.5 mg/ml in the wherein said pharmaceutical composition, the glycerol of 75 mg/ml, the disodium edetate of 1 mg/ml, the boric acid of 5 mg/ml, and the benzalkonium chloride of 0.1 mg/ml, the pH of wherein said compositions are 6.0.

11. local pharmaceutical composition that uses, be used in host, eyelid swelled being treated and preventing, comprise a kind of carrier of medicine acceptability and a kind of infiltrative active agent and a kind of vasoconstrictor of effective dose in the wherein said pharmaceutical composition, wherein said infiltrative active agent is selected from the group of being made up of following reagent place: caffeine, carbomer 934 P, tannic acid, ascorbic acid, Gentran 40 000, inulin, mannitol, menthol, and polysorbate80, and wherein said vasoconstrictor is selected from the group of being made up of following reagent place: naphazoline, oxymetazoline, phenylephrine, and tetrahydrozoline.

12. method of in host, eyelid swelled being treated and preventing, described method comprises: use a kind of compositions on described host's ocular surface, the infiltrative active agent and a kind of vasoconstrictor that comprise a kind of effective dose in the described compositions, the sodium chloride that wherein said infiltrative active agent is 3% weight/volume or the glycerol of 7.5% weight/volume, and vasoconstrictor is the naphazoline of 0.09% weight/volume or the oxymetazoline of 0.05% weight/volume.

13. according to the method described in the claim 12, wherein said osmotic agent is that the glycerol and the described vasoconstrictor of 7.5% weight/volume is the naphazoline of 0.09% weight/volume.

14. according to the method described in the claim 12, wherein said osmotic agent is that the glycerol and the described vasoconstrictor of 7.5% weight/volume is the oxymetazoline of 0.05% weight/volume.

15. according to the method described in the claim 12, wherein said osmotic agent is that the sodium chloride and the described vasoconstrictor of 3% weight/volume is the naphazoline of 0.09% weight/volume.

16. according to the method described in the claim 12, wherein said osmotic agent is that the sodium chloride and the described vasoconstrictor of 3% weight/volume is the oxymetazoline of 0.05% weight/volume.

17. method of in host, eyelid swelled being treated and preventing, described method comprises: use a kind of compositions on described host's ocular surface, the infiltrative active agent and a kind of vasoconstrictor that comprise a kind of effective dose in the described compositions, wherein said infiltrative active agent is selected from the group of being made up of following reagent place: caffeine, carbomer 934 P, tannic acid, ascorbic acid, Gentran 40 000, inulin, mannitol, menthol, and polysorbate80, and wherein said vasoconstrictor is selected from the group of being made up of following reagent place: naphazoline, oxymetazoline, phenylephrine, and tetrahydrozoline.

18. test kit that comprises any described pharmaceutical composition among claim 1 or the claim 7-11.